SUBSTITUTED IMIDAZO[1,2-b]PYRIDAZINES, SUBSTITUTED IMIDAZO[1,5-b]PYRIDAZINES, RELATED COMPOUNDS, AND THEIR USE IN THE TREATMENT OF MEDICAL DISORDERS

ABSTRACT

The invention provides substituted imidazo[1,2-b]pyridazine compounds, substituted imidazo[1,5-b]pyridazine compounds, related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat medical disorders, e.g., Gaucher disease, Parkinson&#39;s disease, Lewy body disease, dementia, or multiple system atrophy, in a patient. Exemplary substituted imidazo[1,2-b]pyridazine compounds described herein include substituted imidazo[1,2-b]pyridazine-3-carboxamide compounds and variants thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalPatent Application Ser. No. 62/332,151, filed May 5, 2016, the contentsof which are hereby incorporated by reference.

FIELD OF THE INVENTION

The invention provides substituted imidazo[1,2-b]pyridazine compounds,substituted imidazo[1,5-b]pyridazine compounds, related compounds,compositions containing such compounds, medical kits, and methods forusing such compounds and compositions to treat medical disorders in apatient.

BACKGROUND

Gaucher disease is a genetic disorder associated with a deficiency ofthe lysosomal enzyme, glucocerebrosidase. Gaucher disease has beenreported to have an incidence of approximately 1 in 20,000 live birthsin the general population, and it is a common lysosomal storagedisorder. Current treatments for patients suffering from this diseaseinclude enzyme replacement therapy, which tends to be expensive,analgesics for bone pain relief, and medical procedures such as bloodand platelet transfusions, splenectomy, and joint replacement forpatients who experience bone erosion. However, new treatment options areneeded having improved efficacy across a broader range of patientsand/or reduced adverse side effects.

Mutations in the gene encoding glucocerebrosidase are also a risk factorfor Parkinson's disease and diffuse Lewy Body Disease. Parkinson'sdisease is a degenerative disorder of the central nervous systemassociated with death of dopamine-containing cells in a region of themidbrain. Parkinson's disease afflicts millions of people, and theincidence of the disease increases with age. Treatment of Parkinson'sdisease frequently involves use of levodopa and dopamine agonists.However, these drugs can produce significant side effects such ashallucinations, insomnia, nausea, and constipation. Further, patientsoften develop tolerance to these drugs such that the drugs becomeineffective at treating the symptoms of the disease, while sometimesalso producing a movement disorder side effect called dyskinesia.Diffuse Lewy Body disease is a dementia that is sometimes confused withAlzheimer's disease.

Accordingly, the need exists for new therapeutic agents for treatingGaucher disease, Parkinson's disease, and related medical disorders. Thepresent invention addresses this need and provides other relatedadvantages.

SUMMARY

The invention provides substituted imidazo[1,2-b]pyridazine compounds,substituted imidazo[1,5-b]pyridazine compounds, related compounds,compositions containing such compounds, medical kits, and methods forusing such compounds and compositions to treat medical disorders, e.g.,Gaucher disease, Parkinson's disease, Lewy body disease, dementia,multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, ananxiety disorder, major depression, polycystic kidney disease, type 2diabetes, open angle glaucoma, multiple sclerosis, endometriosis, andmultiple myeloma, in a patient. Various aspects and embodiments of theinvention are described in further detail below.

Accordingly, one aspect of the invention provides a family ofsubstituted imidazo[1,2-b]pyridazine compounds embraced by Formula Ithat may be used in the methods, compositions, and kits describedherein, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description.

Another aspect of the invention provides a family of substitutedimidazo[1,2-b]pyridazine compounds embraced by Formula II that may beused in the methods, compositions, and kits described herein, whereinFormula II is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description.

Another aspect of the invention provides a family of substitutedimidazo[1,5-b]pyridazine compounds embraced by Formula III that may beused in the methods, compositions, and kits described herein, whereinFormula III is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description.

Another aspect of the invention provides a family of compounds embracedby Formula IV that may be used in the methods, compositions, and kitsdescribed herein, wherein Formula IV is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description.

Another aspect of the invention provides a family of compounds embracedby Formula V that may be used in the methods, compositions, and kitsdescribed herein, wherein Formula V is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description.

Another aspect of the invention provides a family of compounds embracedby Formula VI that may be used in the methods, compositions, and kitsdescribed herein, wherein Formula VI is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description.

Another aspect of the invention provides a family of compounds embracedby Formula VII that may be used in the methods, compositions, and kitsdescribed herein, wherein Formula VII is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description.

Another aspect of the invention provides a pharmaceutical composition,comprising a pharmaceutically acceptable carrier and a substitutedimidazo[1,2-b]pyridazine compound, substituted imidazo[1,5-b]pyridazinecompound, or related compound described herein, such as a compound ofFormula I, II, III, IV, V, VI, or VII. In certain embodiments, theinvention provides a pharmaceutical composition, comprising apharmaceutically acceptable carrier and a substitutedimidazo[1,2-b]pyridazine compound described herein, such as a compoundof Formula I or II. In certain other embodiments, the invention providesa pharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a substituted imidazo[1,5-b]pyridazine compound describedherein, such as a compound of Formula III.

Another aspect of the invention provides a method of treating adisorder, e.g., Gaucher disease, Parkinson's disease, Lewy body disease,dementia, multiple system atrophy, epilepsy, bipolar disorder,schizophrenia, an anxiety disorder, major depression, polycystic kidneydisease, type 2 diabetes, open angle glaucoma, multiple sclerosis,endometriosis, and multiple myeloma, in a patient. The method comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a substituted imidazo[1,2-b]pyridazine compound, substitutedimidazo[1,5-b]pyridazine compound, or related compound described herein,such as a compound of Formula I, II, III, IV, V, VI, or VII, to treatthe disorder, e.g., Gaucher disease, Parkinson's disease, Lewy bodydisease, dementia, multiple system atrophy, epilepsy, bipolar disorder,schizophrenia, an anxiety disorder, major depression, polycystic kidneydisease, type 2 diabetes, open angle glaucoma, multiple sclerosis,endometriosis, or multiple myeloma.

DETAILED DESCRIPTION

The invention provides substituted imidazo[1,2-b]pyridazine compounds,substituted imidazo[1,5-b]pyridazine compounds, related compounds,compositions containing such compounds, medical kits, and methods forusing such compounds and compositions to treat medical disorders in apatient. The practice of the present invention employs, unless otherwiseindicated, conventional techniques of organic chemistry, pharmacology,cell biology, and biochemistry. Such techniques are explained in theliterature, such as in “Comprehensive Organic Synthesis” (B. M. Trost &I. Fleming, eds., 1991-1992); “Current protocols in molecular biology”(F. M. Ausubel et al., eds., 1987, and periodic updates); and “Currentprotocols in immunology” (J. E. Coligan et al., eds., 1991), each ofwhich is herein incorporated by reference in its entirety. Variousaspects of the invention are set forth below in sections; however,aspects of the invention described in one particular section are not tobe limited to any particular section.

I. Definitions

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The terms “a” and “an” as used herein mean “one or more” and include theplural unless the context is inappropriate.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-12,1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂alkyl,C₁-C₁₀alkyl, and C₁-C₆alkyl, respectively. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,etc.

The term “alkylene” refers to a diradical of an alkyl group. Anexemplary alkylene group is —CH₂CH₂—.

The term “haloalkyl” refers to an alkyl group that is substituted withat least one halogen. For example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CF₂CF₃,and the like.

The term “haloalkylene” refers to a diradical of a haloalkyl group.Exemplary haloalkylene groups are —CH₂CF₂— and —C(H)(CF₃)CH₂—.

The term “heteroalkyl” as used herein refers to an “alkyl” group inwhich at least one carbon atom has been replaced with a heteroatom(e.g., an O, N, or S atom). The heteroalkyl may be, for example, an—O—C₁-C₁₀alkyl group, an —C₁-C₆alkylene-O—C₁-C₆alkyl group, or a C₁-C₆alkylene-OH group. In certain embodiments, the “heteroalkyl” may be 2-8membered heteroalkyl, indicating that the heteroalkyl contains from 2 to8 atoms selected from the group consisting of carbon, oxygen, nitrogen,and sulfur. In yet other embodiments, the heteroalkyl may be a 2-6membered, 4-8 membered, or a 5-8 membered heteroalkyl group (which maycontain for example 1 or 2 heteroatoms selected from the group oxygenand nitrogen). One type of heteroalkyl group is an “alkoxyl” group.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond, suchas a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms,referred to herein as C₂-C₁₂alkenyl, C₂-C₁₀alkenyl, and C₂-C₆alkenyl,respectively. Exemplary alkenyl groups include vinyl, allyl, butenyl,pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl, and the like.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond, suchas a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms,referred to herein as C₂-C₁₂alkynyl, C₂-C₁₀alkynyl, and C₂-C₆alkynyl,respectively. Exemplary alkynyl groups include ethynyl, prop-1-yn-1-yl,and but-1-yn-1-yl.

The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic,or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8,or 4-6 carbons, referred to herein, e.g., as “C₄₋₈cycloalkyl,” derivedfrom a cycloalkane. Unless specified otherwise, the cycloalkyl group isoptionally substituted by 1 or 2 C₁-C₆ alkyl groups. In certainembodiments, the cycloalkyl group is unsubstituted. Exemplary cycloalkylgroups include, but are not limited to, cyclohexanes, cyclopentanes,cyclobutanes and cyclopropanes.

The term “cycloalkylene” refers to a diradical of an cycloalkyl group.An exemplary cycloalkylene group is

The term “cycloalkenyl” as used herein refers to a monovalentunsaturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl)hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons containing onecarbon-carbon double bond, referred to herein, e.g., as“C₄₋₈cycloalkenyl,” derived from a cycloalkane. Exemplary cycloalkenylgroups include, but are not limited to, cyclohexenes, cyclopentenes, andcyclobutenes. Unless specified otherwise, cycloalkenyl groups areoptionally substituted at one or more ring positions with, for example,alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl,arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl,ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato,sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. In certainembodiments, the cycloalkenyl group is not substituted, i.e., it isunsubstituted.

The term “aryl” is art-recognized and refers to a carbocyclic aromaticgroup. Representative aryl groups include phenyl, naphthyl, anthracenyl,and the like. The term “aryl” includes polycyclic ring systems havingtwo or more carbocyclic rings in which two or more carbons are common totwo adjoining rings (the rings are “fused rings”) wherein at least oneof the rings is aromatic and, e.g., the other ring(s) may becycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls. Unlessspecified otherwise, the aromatic ring may be substituted at one or morering positions with, for example, halogen, azide, alkyl, aralkyl,alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl, —CO₂alkyl,carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide,ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties,—CF₃, —CN, or the like. In certain embodiments, the aromatic ring issubstituted at one or more ring positions with halogen, alkyl, hydroxyl,or alkoxyl. In certain other embodiments, the aromatic ring is notsubstituted, i.e., it is unsubstituted. In certain embodiments, the arylgroup is a 6-10 membered ring structure.

The term “aralkyl” refers to an alkyl group substituted with an arylgroup.

The term “bicyclic carbocyclyl that is partially unsaturated” refers toa bicyclic carbocyclic group containing at least one double bond betweenring atoms and at least one ring in the bicyclic carbocyclic group isnot aromatic. Representative examples of a bicyclic carbocyclyl that ispartially unsaturated include, for example:

The terms ortho, meta and para are art-recognized and refer to 1,2-,1,3- and 1,4-disubstituted benzenes, respectively. For example, thenames 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms “heterocyclyl” and “heterocyclic group” are art-recognized andrefer to saturated, partially unsaturated, or aromatic 3- to 10-memberedring structures, alternatively 3- to 7-membered rings, whose ringstructures include one to four heteroatoms, such as nitrogen, oxygen,and sulfur. The number of ring atoms in the heterocyclyl group can bespecified using C_(x)-C_(x) nomenclature where x is an integerspecifying the number of ring atoms. For example, a C₃-C₇heterocyclylgroup refers to a saturated or partially unsaturated 3- to 7-memberedring structure containing one to four heteroatoms, such as nitrogen,oxygen, and sulfur. The designation “C₃-C₇” indicates that theheterocyclic ring contains a total of from 3 to 7 ring atoms, inclusiveof any heteroatoms that occupy a ring atom position. One example of aC₃heterocyclyl is aziridinyl. Heterocycles may also be mono-, bi-, orother multi-cyclic ring systems. A heterocycle may be fused to one ormore aryl, partially unsaturated, or saturated rings. Heterocyclylgroups include, for example, biotinyl, chromenyl, dihydrofuryl,dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl,homopiperidinyl, imidazolidinyl, isoquinolyl, isothiazolidinyl,isooxazolidinyl, morpholinyl, oxolanyl, oxazolidinyl, phenoxanthenyl,piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl,tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl,tetrahydroquinolyl, thiazolidinyl, thiolanyl, thiomorpholinyl,thiopyranyl, xanthenyl, lactones, lactams such as azetidinones andpyrrolidinones, sultams, sultones, and the like. Unless specifiedotherwise, the heterocyclic ring is optionally substituted at one ormore positions with substituents such as alkanoyl, alkoxy, alkyl,alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido,carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl,halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone,nitro, oxo, phosphate, phosphonato, phosphinato, sulfate, sulfide,sulfonamido, sulfonyl and thiocarbonyl. In certain embodiments, theheterocyclyl group is not substituted, i.e., it is unsubstituted.

The term “oxoheterocyclyl” refers to a heterocyclyl group that issubstituted with at least one oxo group (i.e., ═O). In certainembodiments, the oxoheterocyclyl is substituted with 1 or 2 oxo groups.In certain embodiments, the oxoheterocyclyl is a 5-6 membered saturatedheterocyclyl substituted with 1 oxo group.

The term “bicyclic heterocyclyl” refers to a heterocyclyl group thatcontains two rings that are fused together. Representative examples of abicyclic heterocyclyl include, for example:

In certain embodiments, the bicyclic heterocyclyl is an carbocyclic ringfused to partially unsaturated heterocyclic ring, that together form abicyclic ring structure having 8-10 ring atoms (e.g., where there are 1,2, 3, or 4 heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur).

The term “heterocycloalkyl” is art-recognized and refers to a saturatedheterocyclyl group as defined above. In certain embodiments, the“heterocycloalkyl” is a 3- to 10-membered ring structures, alternativelya 3- to 7-membered rings, whose ring structures include one to fourheteroatoms, such as nitrogen, oxygen, and sulfur.

The term “heterocycloalkylene” refers to a diradical of aheterocycloalkyl group. An exemplary heterocycloalkylene group is

The heterocycloalkylene may contain, for example, 3-6 ring atom (i.e., a3-6 membered heterocycloalkylene). In certain embodiments, theheterocycloalkylene is a 3-6 membered heterocycloalkylene containing 1,2, or 3 three heteroatoms selected from the group consisting of oxygen,nitrogen, and sulfur.

The term “heteroaryl” is art-recognized and refers to aromatic groupsthat include at least one ring heteroatom. In certain instances, aheteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representativeexamples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl,imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl,pyrazinyl, pyridazinyl and pyrimidinyl, and the like. Unless specifiedotherwise, the heteroaryl ring may be substituted at one or more ringpositions with, for example, halogen, azide, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino,amido, carboxylic acid, —C(O)alkyl, —CO₂alkyl, carbonyl, carboxyl,alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester,heterocyclyl, aryl or heteroaryl moieties, —CF₃, —CN, or the like. Theterm “heteroaryl” also includes polycyclic ring systems having two ormore rings in which two or more carbons are common to two adjoiningrings (the rings are “fused rings”) wherein at least one of the rings isheteroaromatic, e.g., the other cyclic rings may be cycloalkyls,cycloalkenyls, cycloalkynyls, and/or aryls. In certain embodiments, theheteroaryl ring is substituted at one or more ring positions withhalogen, alkyl, hydroxyl, or alkoxyl. In certain other embodiments, theheteroaryl ring is not substituted, i.e., it is unsubstituted. Incertain embodiments, the heteroaryl group is a 5- to 10-membered ringstructure, alternatively a 5- to 6-membered ring structure, whose ringstructure includes 1, 2, 3, or 4 heteroatoms, such as nitrogen, oxygen,and sulfur.

The term “heteroaralkyl” refers to an alkyl group substituted with aheteroaryl group.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety represented by thegeneral formula —N(R⁵⁰)(R⁵¹), wherein R⁵⁰ and R⁵¹ each independentlyrepresent hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl,aralkyl, or —(CH₂)_(m)—R⁶¹; or R⁵⁰ and R⁵¹, taken together with the Natom to which they are attached complete a heterocycle having from 4 to8 atoms in the ring structure; R⁶¹ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle or a polycycle; and m is zero or an integerin the range of 1 to 8. In certain embodiments, R⁵⁰ and R⁵¹ eachindependently represent hydrogen, alkyl, alkenyl, or —(CH₂)_(m)—R⁶¹.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as may berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl,—O—(CH₂)_(m)—R₆₁, where m and R₆₁ are described above.

The term “carbamate” as used herein refers to a radical of the form—R_(g)OC(O)N(R_(h))—, —R_(g)OC(O)N(R_(h))R_(i)—, or —OC(O)NR_(h)R_(i),wherein R_(g), R_(h) and R_(i) are each independently alkoxy, aryloxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, nitro, sulfide, sulfonyl, orsulfonamide. Exemplary carbamates include arylcarbamates and heteroarylcarbamates, e.g., wherein at least one of R_(g), R_(h) and R_(i) areindependently aryl or heteroaryl, such as phenyl and pyridinyl.

The term “carbonyl” as used herein refers to the radical —C(O)—.

The term “carboxamido” as used herein refers to the radical —C(O)NRR′,where R and R′ may be the same or different. R and R′ may beindependently alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl,heteroaryl, or heterocyclyl.

The term “carboxy” as used herein refers to the radical —COOH or itscorresponding salts, e.g. —COONa, etc.

The term “amide” or “amido” as used herein refers to a radical of theform —R_(a)C(O)N(R_(b))—, —R_(a)C(O)N(R_(b))R_(c)—, —C(O)NR_(b)R_(c), or—C(O)NH₂, wherein R_(a), R_(b) and R_(c) are each independently alkoxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydrogen, hydroxyl, ketone, or nitro. The amide can beattached to another group through the carbon, the nitrogen, R_(b),R_(c), or R_(a). The amide also may be cyclic, for example R_(b) andR_(c), R_(a) and R_(b), or R_(a) and R_(c) may be joined to form a 3- to12-membered ring, such as a 3- to 10-membered ring or a 5- to 6-memberedring.

The term “amidino” as used herein refers to a radical of the form—C(═NR)NR′R″ where R, R′, and R″ are each independently alkyl, alkenyl,alkynyl, amide, aryl, arylalkyl, cyano, cycloalkyl, haloalkyl,heteroaryl, heterocyclyl, hydroxyl, ketone, or nitro.

The term “alkanoyl” as used herein refers to a radical —O—CO-alkyl.

The term “oxo” is art-recognized and refers to a “═O” substituent. Forexample, a cyclopentane substituted with an oxo group is cyclopentanone.

The term “sulfonamide” or “sulfonamido” as used herein refers to aradical having the structure —N(R_(r))—S(O)₂—R_(s)— or—S(O)₂—N(R_(r))R_(s), where R_(r), and R_(s) can be, for example,hydrogen, alkyl, aryl, cycloalkyl, and heterocyclyl. Exemplarysulfonamides include alkylsulfonamides (e.g., where R_(s) is alkyl),arylsulfonamides (e.g., where R_(s) is aryl), cycloalkyl sulfonamides(e.g., where R_(s) is cycloalkyl), and heterocyclyl sulfonamides (e.g.,where R_(s) is heterocyclyl), etc.

The term “sulfonyl” as used herein refers to a radical having thestructure R_(u)SO₂—, where R_(s) can be alkyl, aryl, cycloalkyl, andheterocyclyl, e.g., alkylsulfonyl. The term “alkylsulfonyl” as usedherein refers to an alkyl group attached to a sulfonyl group.

The symbol “

” indicates a point of attachment.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly. It is understood that graphical depictions ofchemical structures, e.g., generic chemical structures, encompass allstereoisomeric forms of the specified compounds, unless indicatedotherwise.

Individual stereoisomers of compounds of the present invention can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers bywell-known methods, such as chiral-phase gas chromatography,chiral-phase high performance liquid chromatography, crystallizing thecompound as a chiral salt complex, or crystallizing the compound in achiral solvent. Further, enantiomers can be separated usingsupercritical fluid chromatographic (SFC) techniques described in theliterature. Still further, stereoisomers can be obtained fromstereomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

Geometric isomers can also exist in the compounds of the presentinvention. The symbol

denotes a bond that may be a single, double or triple bond as describedherein. The present invention encompasses the various geometric isomersand mixtures thereof resulting from the arrangement of substituentsaround a carbon-carbon double bond or arrangement of substituents arounda carbocyclic ring. Substituents around a carbon-carbon double bond aredesignated as being in the “Z” or “E” configuration wherein the terms“Z” and “E” are used in accordance with IUPAC standards. Unlessotherwise specified, structures depicting double bonds encompass boththe “E” and “Z” isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

The invention also embraces isotopically labeled compounds of theinvention which are identical to those recited herein, except that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as ²H, ³H, ³C, ¹⁴C, ⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁹F, and ³⁶Cl, respectively.

Certain isotopically-labeled disclosed compounds (e.g., those labeledwith ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed in, e.g., the Examples herein by substituting an isotopicallylabeled reagent for a non-isotopically labeled reagent.

As used herein, the terms “subject” and “patient” refer to organisms tobe treated by the methods of the present invention. Such organisms arepreferably mammals (e.g., murines, simians, equines, bovines, porcines,canines, felines, and the like), and more preferably humans.

As used herein, the term “effective amount” refers to the amount of acompound (e.g., a compound of the present invention) sufficient toeffect beneficial or desired results. An effective amount can beadministered in one or more administrations, applications or dosages andis not intended to be limited to a particular formulation oradministration route. As used herein, the term “treating” includes anyeffect, e.g., lessening, reducing, modulating, ameliorating oreliminating, that results in the improvement of the condition, disease,disorder, and the like, or ameliorating a symptom thereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as an oil/wateror water/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants, see Martin, Remington'sPharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. [1975].

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metal (e.g.,sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.Other examples of salts include anions of the compounds of the presentinvention compounded with a suitable cation such as Na⁺, NH₄ ⁺, and NW₄⁺ (wherein W is a C₁₋₄ alkyl group), and the like.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

Abbreviations as used herein may includeO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); diisopropylethylamine (DIPEA);dimethylformamide (DMF); methylene chloride (DCM); tert-butoxycarbonyl(Boc); tetrahydrofuran (THF); trifluoroacetic acid (TFA);N-methylmorpholine (NMM); triethylamine (TEA); Boc anhydride ((Boc)₂O);dimethylsulfoxide (DMSO); diisopropylethylamine (DIEA);N,N-Dimethylpyridin-4-amine (DMAP); flash column chromatography (FCC);and supercritical fluid chromatography (SFC).

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present invention that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present invention that consist essentially of, orconsist of, the recited processing steps.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified. Further, if a variable is not accompanied bya definition, then the previous definition of the variable controls.

II. Substituted Imidazo[1,2-B]Pyridazine, SubstitutedImidazo[1,5-B]Pyridazine, and Related Compounds

One aspect of the invention provides substitutedimidazo[1,2-b]pyridazine compounds. The substitutedimidazo[1,2-b]pyridazine compounds are contemplated to be useful in themethods, compositions, and kits described herein. In certainembodiments, the substituted imidazo[1,2-b]pyridazine compound is acompound embraced by Formula I:

R^(1A) is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, 3-10 memberedheterocyclyl, or 6-membered aryl, wherein the cycloalkyl, heterocyclyl,and aryl are optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, cyano,—N(R⁵)₂, —C(O)—(C₁-C₆ alkyl), —N(R⁵)C(O)—(C₁-C₆ alkyl), and —C(O)N(R⁵)₂;

R^(1B) represents independently for each occurrence C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, —(C₁-C₄alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄ alkylene)-O—(C₃-C₆ cycloalkyl), 3-6membered heterocyclyl, 6-membered aryl, cyano, or —N(R⁵)₂;

R² is hydrogen, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,C₁-C₆ alkoxy, —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄alkylene)-O—(C₃-C₆ cycloalkyl), 3-6 membered heterocyclyl, 6-memberedaryl, cyano, or —N(R⁵)₂;

R³ is hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;

R⁴ is one of the following:

-   -   C₃-C₈ cycloalkyl, 3-8 membered heterocycloalkyl, 9-13 membered        spiroheterocycloalkyl, —(C₂-C₆ alkylene)-O-phenyl, phenyl,        heteroaryl, a partially unsaturated 9-10 membered bicyclic        carbocyclyl, or a partially unsaturated 8-10 membered bicyclic        heterocyclyl; each of which is optionally substituted by 1, 2,        or 3 substituents independently selected from the group        consisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆        cycloalkyl, —(C₁-C₆ alkylene)-(C₃-C₆ cycloalkyl), hydroxyl,        C₁-C₆ alkoxy, C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy,        —O—(C₃-C₆ cycloalkyl), aryl, —O-aryl, heteroaryl, saturated 3-8        membered heterocyclyl, amino, and —CO₂R⁵; or    -   C₁₋₆ alkyl or C₂₋₆ alkynyl;

R⁵ represents independently for each occurrence hydrogen, C₁-C₆ alkyl,or C₃-C₆ cycloalkyl; or two occurrences of R⁵ attached to the samenitrogen atom are taken together with the nitrogen atom to which theyare attached to form a 3-8 membered heterocyclic ring; Y is a bond,—C(O)—, C₁-C₆ haloalkylene, C₃-C₆ cycloalkylene, or C₁-C₆ alkyleneoptionally substituted with C₃-C₆ cycloalkylene; and

n is 0, 1, or 2;

provided that when Y—R⁴ is —CH₂-phenyl, then n is 1 or 2.

Definitions of the variables in Formula I above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where R^(1A) is C₁-C₆ alkyl, R² is hydrogen, and R⁴ is C₃-C₈cycloalkyl or phenyl; each of which is optionally substituted by 1, 2,or 3 substituents independently selected from the group consisting ofC₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, and C₃-C₆ cycloalkyl.

Accordingly, in certain embodiments, R^(1A) is C₁-C₆ alkyl. In certainembodiments, R^(1A) is C₁-C₃ alkyl, 3-6 membered heterocyclyl, or6-membered aryl, wherein the heterocyclyl and aryl are optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy. In certain embodiments, R^(1A) isC₁-C₃ alkyl. In certain embodiments, R^(1A) is methyl. In certainembodiments, R^(1A) is 6-membered aryl optionally substituted with 1, 2,or 3 substituents independently selected from the group consisting ofhalogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆alkoxy, and cyano. In certain embodiments, R^(1A) is 6-membered arylsubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, and cyano. In certain embodiments, R^(1A) is 6-membered arylsubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, C₁-C₆ haloalkyl, and cyano. In certainembodiments, R^(1A) is attached at the 6-position of theimidazo[1,2-b]pyridazinyl group of Formula I.

In certain embodiments, R^(1B) represents independently for eachoccurrence C₁-C₆ alkyl or halogen. In certain embodiments, R^(1B)represents independently for each occurrence C₁-C₃ alkyl or halogen. Incertain embodiments, R^(1B) IS C₁-C₆ alkyl. In certain embodiments,R^(1B) is C₁-C₃ alkyl. In certain embodiments, R^(1B) is halogen.

In certain embodiments, R^(1A) and R^(1B) are C₁-C₃ alkyl. In certainembodiments, R^(1A) and R^(1B) are methyl. In certain embodiments,R^(1A) is methyl, and R^(1B) is chloro or fluoro.

In certain embodiments, R² is hydrogen.

In certain embodiments, R³ is hydrogen.

In certain embodiments, Y is a bond. In certain embodiments, Y is C₁-C₆alkylene. In certain embodiments, Y is C₁-C₆ haloalkylene.

In certain embodiments, R⁴ is C₃-C₈ cycloalkyl optionally substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —(C₁-C₆alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆ alkoxy, C₂-C₄ alkynyl,—(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, —O-aryl, heteroaryl, saturated 3-8membered heterocyclyl, amino, and —CO₂R⁵. In certain embodiments, R⁴ isC₃-C₈ cycloalkyl optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy. In certainembodiments, R⁴ is C₄-C₆ cycloalkyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy. In certainembodiments, R⁴ is C₃-C₈ cycloalkyl optionally substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₈alkyl and C₁-C₆ haloalkyl. In certain embodiments, R⁴ is C₃-C₈cycloalkyl.

In certain embodiments, R⁴ is a partially unsaturated 9-10 memberedbicyclic carbocyclyl optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, heteroaryl, andsaturated 3-8 membered heterocyclyl. In certain embodiments, R⁴ is apartially unsaturated 9-10 membered bicyclic carbocyclyl optionallysubstituted by C₁-C₆ alkyl.

In certain embodiments, R⁴ is phenyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₆alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆alkoxy, C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, 5-memberedheteroaryl, and saturated 3-8 membered heterocyclyl. In certainembodiments, R⁴ is phenyl substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy. In certainembodiments, R⁴ is phenyl substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₄ alkynyl, and —(C₂-C₄alkynyl)-C₁-C₆ alkoxy.

In certain embodiments, R⁴ is C₁-C₆ alkyl.

In certain embodiments, n is 2. In certain embodiments, n is 1. Incertain embodiments, n is 0.

The description above describes multiple embodiments relating tocompounds of Formula I. The patent application specifically contemplatesall combinations of the embodiments.

In certain embodiments, the substituted imidazo[1,2-b]pyridazinecompound is a compound embraced by Formula I-1:

or a pharmaceutically acceptable salt thereof, wherein:

R^(1A) is C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₃-C₆ cycloalkyl;

R^(1B) represents independently for each occurrence C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, or C₃-C₆ cycloalkyl;

R² is hydrogen, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, or C₃-C₆cycloalkyl;

R³ is hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;

R⁴ is C₃-C₈ cycloalkyl, 3-8 membered heterocycloalkyl, 9-13 memberedspiroheterocycloalkyl, —(C₂-C₆ alkylene)-O-phenyl, phenyl, heteroaryl, apartially unsaturated 9-10 membered bicyclic carbocyclyl, or a partiallyunsaturated 8-10 membered bicyclic heterocyclyl; each of which isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl,C₃-C₆ cycloalkyl, —(C₁-C₆ alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆alkoxy, C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, —O-aryl,heteroaryl, saturated 3-8 membered heterocyclyl, amino, and —CO₂R⁵;

R⁵ represents independently for each occurrence hydrogen, C₁-C₆ alkyl,or C₃-C₆ cycloalkyl;

Y is a bond or C₁-C₆ alkylene; and

n is 0, 1, or 2;

provided that when Y—R⁴ is —CH₂-phenyl, then n is 1 or 2.

Definitions of the variables in Formula I-1 above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where R^(1A) is C₁-C₆ alkyl, R² is hydrogen, and R⁴ is C₃-C₈cycloalkyl or phenyl; each of which is optionally substituted by 1, 2,or 3 substituents independently selected from the group consisting ofC₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, and C₃-C₆ cycloalkyl.

Accordingly, in certain embodiments, R^(1A) is C₁-C₆ alkyl. In certainembodiments, R is C₁-C₃ alkyl. In certain embodiments, R^(1A) is methyl.

In certain embodiments, R^(1B) represents independently for eachoccurrence C₁-C₆ alkyl or halogen. In certain embodiments, R^(1B)represents independently for each occurrence C₁-C₃ alkyl or halogen. Incertain embodiments, R^(1B) IS C₁-C₆ alkyl. In certain embodiments,R^(1B) is C₁-C₃ alkyl. In certain embodiments, R^(1B) is halogen.

In certain embodiments, R^(1A) and R^(1B) are C₁-C₃ alkyl. In certainembodiments, R^(1A) and R^(1B) are methyl. In certain embodiments,R^(1A) is methyl, and R^(1B) is chloro or fluoro.

In certain embodiments, R² is hydrogen.

In certain embodiments, R³ is hydrogen.

In certain embodiments, Y is a bond. In certain embodiments, Y is C₁-C₆alkylene.

In certain embodiments, R⁴ is C₃-C₈ cycloalkyl optionally substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —(C₁-C₆alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆ alkoxy, C₂-C₄ alkynyl,—(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, —O-aryl, heteroaryl, saturated 3-8membered heterocyclyl, amino, and —CO₂R⁵. In certain embodiments, R⁴ isC₃-C₈ cycloalkyl optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy. In certainembodiments, R⁴ is C₄-C₆ cycloalkyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy.

In certain embodiments, R⁴ is a partially unsaturated 9-10 memberedbicyclic carbocyclyl optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, heteroaryl, andsaturated 3-8 membered heterocyclyl. In certain embodiments, R⁴ is apartially unsaturated 9-10 membered bicyclic carbocyclyl optionallysubstituted by C₁-C₆ alkyl.

In certain embodiments, R⁴ is phenyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₆alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆alkoxy, C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, 5-memberedheteroaryl, and saturated 3-8 membered heterocyclyl. In certainembodiments, R⁴ is phenyl substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy. In certainembodiments, R⁴ is phenyl substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₄ alkynyl, and —(C₂-C₄alkynyl)-C₁-C₆ alkoxy.

In certain embodiments, n is 2. In certain embodiments, n is 1. Incertain embodiments, n is 0.

The description above describes multiple embodiments relating tocompounds of Formula I-1. The patent application specificallycontemplates all combinations of the embodiments.

In certain embodiments, the compound is a compound of Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein:

R^(1A) is C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, or C₃-C₆ cycloalkyl;

R^(1B) and R² are independently hydrogen, C₁-C₆ alkyl, halogen, C₁-C₆haloalkyl, or C₃-C₆ cycloalkyl;

R^(1C) is C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₃-C₆ cycloalkyl;

R³ is hydrogen;

R⁴ is C₃-C₈ cycloalkyl, 3-8 membered heterocycloalkyl, 9-13 memberedspiroheterocycloalkyl, —(C₂-C₆ alkylene)-O-phenyl, phenyl, heteroaryl, apartially unsaturated 9-10 membered bicyclic carbocyclyl, or a partiallyunsaturated 8-10 membered bicyclic heterocyclyl; each of which isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl,C₃-C₆ cycloalkyl, —(C₁-C₆ alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆alkoxy, C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, —O-aryl,heteroaryl, saturated 3-8 membered heterocyclyl, amino, and —CO₂R⁵;

R⁵ represents independently for each occurrence hydrogen, C₁-C₆ alkyl,or C₃-C₆ cycloalkyl; and

Y is a bond, C₁-C₆ alkylene, or C₁-C₆ haloalkylene.

Definitions of the variables in Formula I-A above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where R^(1A) and R^(1C) are C₁-C₆ alkyl, R² is hydrogen, and R⁴is C₃-C₈ cycloalkyl or phenyl; each of which is optionally substitutedby 1, 2, or 3 substituents independently selected from the groupconsisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl.

Accordingly, in certain embodiments, R^(1A) and R^(1C) are methyl. Incertain embodiments, R^(1A) and R^(1C) are C₁-C₃ alkyl. In certainembodiments, R^(1A) is chloro or fluoro, and R^(1C) is methyl. Incertain embodiments, R^(1A) and R^(1C) are methyl, and R^(1B) ishydrogen. In certain embodiments, R^(1A) is halogen, R^(1B) is hydrogen,and R^(1C) is methyl.

In certain embodiments, R² is hydrogen.

In certain embodiments, Y is a bond. In certain embodiments, Y is C₁-C₆alkylene.

In certain embodiments, R⁴ is C₃-C₈ cycloalkyl optionally substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl,C₁-C₆ alkoxy, C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy. Incertain embodiments, R⁴ is C₃-C₈ cycloalkyl optionally substituted by 1,2, or 3 substituents independently selected from the group consisting ofC₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, and C₂-C₄alkynyl. In certain embodiments, R⁴ is C₄-C₆ cycloalkyl substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy. Incertain embodiments, R⁴ is C₄-C₆ cycloalkyl optionally substituted by 1or 2 substituents independently selected from the group consisting ofC₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy.

In certain embodiments, R⁴ is a partially unsaturated 9-10 memberedbicyclic carbocyclyl optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy. In certainembodiments, R⁴ is a partially unsaturated 9-10 membered bicycliccarbocyclyl optionally substituted by C₁-C₆ alkyl.

In certain embodiments, R⁴ is phenyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₆alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆alkoxy, C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy. In certainembodiments, R⁴ is phenyl substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, and C₂-C₄alkynyl. In certain embodiments, R⁴ is phenyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₆alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₄ alkynyl, and—(C₂-C₄ alkynyl)-C₁-C₆ alkoxy. In certain embodiments, R⁴ is C₃-C₈cycloalkyl or phenyl; each of which is optionally substituted by 1, 2,or 3 substituents independently selected from the group consisting ofC₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, and C₃-C₆ cycloalkyl.

The description above describes multiple embodiments relating tocompounds of Formula I-A. The patent application specificallycontemplates all combinations of the embodiments.

In certain embodiments, the compound is a compound of Formula I-B:

or a pharmaceutically acceptable salt thereof, wherein:

R^(1A) is 6-membered aryl substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl, and cyano;

R^(1B) and R² are hydrogen;

R^(1C) is C₁-C₆ alkyl;

R³ is hydrogen;

R⁴ is (i) C₃-C₈ cycloalkyl optionally substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₈alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or (ii) C₁-C₆ alkyl; and

Y is C₁-C₆ alkylene or C₁-C₆ haloalkylene.

Definitions of the variables in Formula I-B above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii).

Accordingly, in certain embodiments, R^(1A) is 6-membered arylsubstituted with 1 or 2 substituents independently selected from thegroup consisting of halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and cyano. Incertain embodiments, R^(1A) is 6-membered aryl substituted with 1 or 2substituents independently selected from the group consisting ofhalogen, C₁-C₃ alkyl, and cyano. In certain embodiments, R^(1A) is6-membered aryl substituted with 1 or 2 substituents independentlyselected from fluorine and cyano. In certain embodiments, R^(1C) isC₁-C₃ alkyl. In certain embodiments, R^(1C) is methyl. In certainembodiments, Y is C₁-C₆ alkylene. In certain embodiments, Y is C₁-C₆haloalkylene. In certain embodiments, R⁴ is C₃-C₈ cycloalkyl. In certainembodiments, R⁴ is C₁-C₆ alkyl. The description above describes multipleembodiments relating to compounds of Formula I-B. The patent applicationspecifically contemplates all combinations of the embodiments.

Another aspect of the invention provides a family of compoundsrepresented by Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

X is halogen;

-   -   R¹ represents independently for each occurrence C₁-C₆ alkyl,        halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy,        —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄ alkylene)-O—(C₃-C₆        cycloalkyl), 3-6 membered heterocyclyl, 6-membered aryl, cyano,        or —N(R⁵)₂;

R² is hydrogen, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,C₁-C₆ alkoxy, —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄alkylene)-O—(C₃-C₆ cycloalkyl), 3-6 membered heterocyclyl, 6-memberedaryl, cyano, or —N(R⁵)₂;

R³ is hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;

R⁴ is one of the following:

-   -   (a) C₃-C₈ cycloalkyl substituted by 1, 2, or 3 substituents        independently selected from the group consisting of C₁-C₈ alkyl,        halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —(C₁-C₆        alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆ alkoxy, —O—(C₃-C₆        cycloalkyl), C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, and        saturated 3-8 membered heterocyclyl;    -   (b) phenyl that is (i) substituted by C₂-C₄ alkynyl or —(C₂-C₄        alkynyl)-C₁-C₆ alkoxy, and (ii) optionally substituted by 1 or 2        substituents independently selected from the group consisting of        C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —(C₁-C₆        alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆ alkoxy, —O—(C₃-C₆        cycloalkyl), heteroaryl, saturated 3-8 membered heterocyclyl,        and amino; or    -   (c) a partially unsaturated 9-10 membered bicyclic carbocyclyl,        a partially unsaturated 8-10 membered bicyclic heterocyclyl, a        3-8 membered heterocycloalkyl, a 9-13 membered        spiroheterocycloalkyl, —(C₂-C₆ alkylene)-O-phenyl, or        heteroaryl; each of which is optionally substituted by 1, 2, or        3 substituents independently selected from the group consisting        of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,        —(C₁-C₆ alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆ alkoxy,        C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, —O—(C₃-C₆        cycloalkyl), aryl, —O-aryl, heteroaryl, saturated 3-8 membered        heterocyclyl, amino, and —CO₂R⁵;

R⁵ represents independently for each occurrence hydrogen, C₁-C₆ alkyl,or C₃-C₆ cycloalkyl; or two occurrences of R⁵ attached to the samenitrogen atom are taken together with the nitrogen atom to which theyare attached to form a 3-8 membered heterocyclic ring; Y is a bond,—C(O)—, C₁-C₆ alkylene, C₁-C₆ haloalkylene, or C₃-C₆ cycloalkylene; and

n is 0, 1, or 2.

Definitions of the variables in Formula II above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where R¹ is C₁-C₆ alkyl, R² is hydrogen, and R⁴ is C₃-C₈cycloalkyl substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl,C₃-C₆ cycloalkyl, —(C₁-C₆ alkylene,)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆alkoxy, C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, and saturated 3-8membered heterocyclyl.

Accordingly, in certain embodiments, R¹ is C₁-C₆ alkyl. In certainembodiments, R¹ is C₁-C₃ alkyl. In certain embodiments, R¹ is methyl.

In certain embodiments, X is chloro. In certain embodiments, X is chloroor fluoro.

In certain embodiments, R² is hydrogen.

In certain embodiments, R³ is hydrogen.

In certain embodiments, Y is a bond. In certain embodiments, Y is C₁-C₆alkylene.

In certain embodiments, R⁴ is C₃-C₈ cycloalkyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₈alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —(C₁-C₆alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆ alkoxy, C₂-C₄ alkynyl,—(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, and saturated 3-8 membered heterocyclyl.In certain embodiments, R⁴ is C₃-C₈ cycloalkyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, and C₂-C₄alkynyl. In certain embodiments, R⁴ is C₄-C₆ cycloalkyl substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy.

In certain embodiments, R⁴ is a partially unsaturated 9-10 memberedbicyclic carbocyclyl optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, heteroaryl, andsaturated 3-8 membered heterocyclyl. In certain embodiments, R⁴ is apartially unsaturated 9-10 membered bicyclic carbocyclyl optionallysubstituted by C₁-C₆ alkyl.

In certain embodiments, R⁴ is phenyl that is (i) substituted by C₂-C₄alkynyl or —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, and (ii) optionallysubstituted by 1 or 2 substituents independently selected from the groupconsisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,—(C₁-C₆ alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, and C₁-C₆ alkoxy. Incertain embodiments, R⁴ is phenyl substituted by C₂-C₄ alkynyl or—(C₂-C₄ alkynyl)-C₁-C₆ alkoxy.

In certain embodiments, n is 2. In certain embodiments, n is 1. Incertain embodiments, n is 0.

The description above describes multiple embodiments relating tocompounds of Formula II. The patent application specificallycontemplates all combinations of the embodiments.

In certain embodiments, the compound is represented by Formula IT-1:

or a pharmaceutically acceptable salt thereof, wherein:

X is halogen;

R¹ represents independently for each occurrence C₁-C₆ alkyl, halogen,C₁-C₆ haloalkyl, or C₃-C₆ cycloalkyl;

R² is hydrogen, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, or C₃-C₆cycloalkyl;

R³ is hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;

R⁴ is one of the following:

-   -   (a) C₃-C₈ cycloalkyl substituted by 1, 2, or 3 substituents        independently selected from the group consisting of C₁-C₈ alkyl,        halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —(C₁-C₆        alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆ alkoxy, C₂-C₄        alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, and saturated 3-8        membered heterocyclyl;    -   (b) phenyl that is (i) substituted by C₂-C₄ alkynyl or —(C₂-C₄        alkynyl)-C₁-C₆ alkoxy, and (ii) optionally substituted by 1 or 2        substituents independently selected from the group consisting of        C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —(C₁-C₆        alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆ alkoxy,        heteroaryl, saturated 3-8 membered heterocyclyl, and amino; or    -   (c) a partially unsaturated 9-10 membered bicyclic carbocyclyl,        a partially unsaturated 8-10 membered bicyclic heterocyclyl, a        3-8 membered heterocycloalkyl, a 9-13 membered        spiroheterocycloalkyl, —(C₂-C₆ alkylene)-O-phenyl, or        heteroaryl; each of which is optionally substituted by 1, 2, or        3 substituents independently selected from the group consisting        of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,        —(C₁-C₆ alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆ alkoxy,        C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, —O-aryl,        heteroaryl, saturated 3-8 membered heterocyclyl, amino, and        —CO₂R⁵;

R⁵ represents independently for each occurrence hydrogen, C₁-C₆ alkyl,or C₃-C₆ cycloalkyl;

Y is a bond or C₁-C₆ alkylene; and

n is 0, 1, or 2.

Definitions of the variables in Formula II-1 above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where R¹ is C₁-C₆ alkyl, R² is hydrogen, and R⁴ is C₃-C₈cycloalkyl substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl,C₃-C₆ cycloalkyl, —(C₁-C₆ alkylene,)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆alkoxy, C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, and saturated 3-8membered heterocyclyl.

Accordingly, in certain embodiments, R¹ is C₁-C₆ alkyl. In certainembodiments, R¹ is C₁-C₃ alkyl. In certain embodiments, R¹ is methyl.

In certain embodiments, X is chloro. In certain embodiments, X is chloroor fluoro.

In certain embodiments, R² is hydrogen.

In certain embodiments, R³ is hydrogen.

In certain embodiments, Y is a bond. In certain embodiments, Y is C₁-C₆alkylene.

In certain embodiments, R⁴ is C₃-C₈ cycloalkyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₈alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —(C₁-C₆alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆ alkoxy, C₂-C₄ alkynyl,—(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, and saturated 3-8 membered heterocyclyl.In certain embodiments, R⁴ is C₃-C₈ cycloalkyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, and C₂-C₄alkynyl. In certain embodiments, R⁴ is C₄-C₆ cycloalkyl substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy.

In certain embodiments, R⁴ is a partially unsaturated 9-10 memberedbicyclic carbocyclyl optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, heteroaryl, andsaturated 3-8 membered heterocyclyl. In certain embodiments, R⁴ is apartially unsaturated 9-10 membered bicyclic carbocyclyl optionallysubstituted by C₁-C₆ alkyl.

In certain embodiments, R⁴ is phenyl that is (i) substituted by C₂-C₄alkynyl or —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, and (ii) optionallysubstituted by 1 or 2 substituents independently selected from the groupconsisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,—(C₁-C₆ alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, and C₁-C₆ alkoxy. Incertain embodiments, R⁴ is phenyl substituted by C₂-C₄ alkynyl or—(C₂-C₄ alkynyl)-C₁-C₆ alkoxy.

In certain embodiments, n is 2. In certain embodiments, n is 1. Incertain embodiments, n is 0.

The description above describes multiple embodiments relating tocompounds of Formula II-1. The patent application specificallycontemplates all combinations of the embodiments.

Another aspect of the invention provides substitutedimidazo[1,5-b]pyridazine compounds. The substitutedimidazo[1,5-b]pyridazine compounds are contemplated to be useful in themethods, compositions, and kits described herein. In certainembodiments, the substituted imidazo[1,5-b]pyridazine compound is acompound embraced by Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

R^(1A) is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, 3-10 memberedheterocyclyl, or 6-membered aryl, wherein the cycloalkyl, heterocyclyl,and aryl are optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, cyano,—N(R⁵)₂, —C(O)—(C₁-C₆ alkyl), —N(R⁵)C(O)—(C₁-C₆ alkyl), and —C(O)N(R⁵)₂;

R^(1B) represents independently for each occurrence C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, —(C₁-C₄alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄ alkylene)-O—(C₃-C₆ cycloalkyl), 3-6membered heterocyclyl, 6-membered aryl, cyano, or —N(R⁵)₂;

R² is hydrogen, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,C₁-C₆ alkoxy, —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄alkylene)-O—(C₃-C₆ cycloalkyl), 3-6 membered heterocyclyl, 6-memberedaryl, cyano, or —N(R⁵)₂;

R³ is hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;

R⁴ is one of the following:

-   -   C₃-C₈ cycloalkyl, 3-8 membered heterocycloalkyl, 9-13 membered        spiroheterocycloalkyl, —(C₂-C₆ alkylene)-O-phenyl, phenyl,        heteroaryl, a partially unsaturated 9-10 membered bicyclic        carbocyclyl, or a partially unsaturated 8-10 membered bicyclic        heterocyclyl; each of which is optionally substituted by 1, 2,        or 3 substituents independently selected from the group        consisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆        cycloalkyl, —(C₁-C₆ alkylene)-(C₃-C₆ cycloalkyl), hydroxyl,        C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), C₂-C₄ alkynyl, —(C₂-C₄        alkynyl)-C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), aryl, —O-aryl,        heteroaryl, saturated 3-8 membered heterocyclyl, amino, and        —CO₂R⁵; or    -   C₁₋₆ alkyl or C₂₋₆ alkynyl;

R⁵ represents independently for each occurrence hydrogen, C₁-C₆ alkyl,or C₃-C₆ cycloalkyl; or two occurrences of R⁵ attached to the samenitrogen atom are taken together with the nitrogen atom to which theyare attached to form a 3-8 membered heterocyclic ring;

Y is a bond, —C(O)—, C₁-C₆ haloalkylene, C₃-C₆ cycloalkylene, or C₁-C₆alkylene optionally substituted with C₃-C₆ cycloalkylene; and

n is 0, 1, or 2.

Definitions of the variables in Formula III above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where R^(1A) is C₁-C₆ alkyl, R² is hydrogen, and R⁴ is C₃-C₈cycloalkyl or phenyl; each of which is optionally substituted by 1, 2,or 3 substituents independently selected from the group consisting ofC₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, and C₃-C₆ cycloalkyl.

Accordingly, in certain embodiments, R^(1A) is C₁-C₆ alkyl. In certainembodiments, R^(1A) is C₁-C₃ alkyl, 3-6 membered heterocyclyl, or6-membered aryl, wherein the heterocyclyl and aryl are optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy. In certain embodiments, R^(1A) isC₁-C₃ alkyl. In certain embodiments, R^(1A) is methyl.

In certain embodiments, R^(1B) represents independently for eachoccurrence C₁-C₆ alkyl or halogen. In certain embodiments, R^(1B)represents independently for each occurrence C₁-C₃ alkyl or halogen. Incertain embodiments, R^(1B) IS C₁-C₆ alkyl. In certain embodiments,R^(1B) is C₁-C₃ alkyl. In certain embodiments, R^(1B) is halogen.

In certain embodiments, R^(1A) and R^(1B) are C₁-C₃ alkyl. In certainembodiments, R^(1A) and R^(1B) are methyl. In certain embodiments,R^(1A) is methyl, and R^(1B) is chloro or fluoro.

In certain embodiments, R² is hydrogen.

In certain embodiments, R³ is hydrogen.

In certain embodiments, Y is a bond. In certain embodiments, Y is C₁-C₆alkylene.

In certain embodiments, R⁴ is C₃-C₈ cycloalkyl optionally substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —(C₁-C₆alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆ alkoxy, C₂-C₄ alkynyl,—(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, —O-aryl, heteroaryl, saturated 3-8membered heterocyclyl, amino, and —CO₂R⁵. In certain embodiments, R⁴ isC₃-C₈ cycloalkyl optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy. In certainembodiments, R⁴ is C₄-C₆ cycloalkyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy.

In certain embodiments, R⁴ is a partially unsaturated 9-10 memberedbicyclic carbocyclyl optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, heteroaryl, andsaturated 3-8 membered heterocyclyl. In certain embodiments, R⁴ is apartially unsaturated 9-10 membered bicyclic carbocyclyl optionallysubstituted by C₁-C₆ alkyl.

In certain embodiments, R⁴ is phenyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₆alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆alkoxy, C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, 5-memberedheteroaryl, and saturated 3-8 membered heterocyclyl. In certainembodiments, R⁴ is phenyl substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy. In certainembodiments, R⁴ is phenyl substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₄ alkynyl, and —(C₂-C₄alkynyl)-C₁-C₆ alkoxy.

In certain embodiments, n is 2. In certain embodiments, n is 1. Incertain embodiments, n is 0.

The description above describes multiple embodiments relating tocompounds of Formula III. The patent application specificallycontemplates all combinations of the embodiments.

Another aspect of the invention provides substituted[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide compounds. Thesubstituted [1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide compounds arecontemplated to be useful in the methods, compositions, and kitsdescribed herein. In certain embodiments, the substituted[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide compound is a compoundembraced by Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, 3-10 memberedheterocyclyl, or 6-membered aryl, wherein the cycloalkyl, heterocyclyl,and aryl are optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, cyano,—N(R⁵)₂, —C(O)—(C₁-C₆ alkyl), —N(R⁵)C(O)—(C₁-C₆ alkyl), and —C(O)N(R⁵)₂;

-   -   R² represents independently for each occurrence C₁-C₆ alkyl,        halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy,        —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄ alkylene)-O—(C₃-C₆        cycloalkyl), 3-6 membered heterocyclyl, 6-membered aryl, cyano,        or —N(R⁵)₂;

R³ is hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;

R⁴ is one of the following:

-   -   C₃-C₈ cycloalkyl, 3-8 membered heterocycloalkyl, 9-13 membered        spiroheterocycloalkyl, —(C₂-C₆ alkylene)-O-phenyl, phenyl,        heteroaryl, a partially unsaturated 9-10 membered bicyclic        carbocyclyl, or a partially unsaturated 8-10 membered bicyclic        heterocyclyl; each of which is optionally substituted by 1, 2,        or 3 substituents independently selected from the group        consisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆        cycloalkyl, —(C₁-C₆ alkylene)-(C₃-C₆ cycloalkyl), hydroxyl,        C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), C₂-C₄ alkynyl, —(C₂-C₄        alkynyl)-C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), aryl, —O-aryl,        heteroaryl, saturated 3-8 membered heterocyclyl, amino, and        —CO₂R⁵; or    -   C₁₋₆ alkyl or C₂₋₆ alkynyl;

R⁵ represents independently for each occurrence hydrogen, C₁-C₆ alkyl,or C₃-C₆ cycloalkyl; or two occurrences of R⁵ attached to the samenitrogen atom are taken together with the nitrogen atom to which theyare attached to form a 3-8 membered heterocyclic ring; Y is a bond,—C(O)—, C₁-C₆ haloalkylene, C₃-C₆ cycloalkylene, or C₁-C₆ alkyleneoptionally substituted with C₃-C₆ cycloalkylene; and

n is 0, 1, or 2

Definitions of the variables in Formula IV above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii).

Accordingly, in certain embodiments, R¹ is C₁-C₃ alkyl, 3-6 memberedheterocyclyl, or 6-membered aryl, wherein the heterocyclyl and aryl areoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy.

In certain embodiments, R² is hydrogen. In certain embodiments, R³ ishydrogen.

In certain embodiments, Y is C₁-C₆ alkylene. In certain embodiments, Yis C₁-C₆ haloalkylene.

In certain embodiments, R⁴ is C₃-C₈ cycloalkyl optionally substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl,C₁-C₆ alkoxy, C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy. Incertain embodiments, R⁴ is a partially unsaturated 9-10 memberedbicyclic carbocyclyl optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, heteroaryl, andsaturated 3-8 membered heterocyclyl. In certain embodiments, R⁴ is apartially unsaturated 9-10 membered bicyclic carbocyclyl optionallysubstituted by C₁-C₆ alkyl. In certain embodiments, R⁴ is phenylsubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, hydroxyl, C₁-C₆ alkoxy, C₂-C₄ alkynyl, —(C₂-C₄alkynyl)-C₁-C₆ alkoxy, 5-membered heteroaryl, and saturated 3-8 memberedheterocyclyl. In certain embodiments, R⁴ is phenyl substituted by 1, 2,or 3 substituents independently selected from the group consisting ofC₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆alkoxy, C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy.

In certain embodiments, n is 1.

The description above describes multiple embodiments relating tocompounds of Formula IV. The patent application specificallycontemplates all combinations of the embodiments.

Another aspect of the invention provides substitutedthieno[3,2-b]pyridine-3-carboxamide and related compounds. Thesubstituted thieno[3,2-b]pyridine-3-carboxamide and related compoundsare contemplated to be useful in the methods, compositions, and kitsdescribed herein. In certain embodiments, the substitutedthieno[3,2-b]pyridine-3-carboxamide or related compound is a compoundembraced by Formula V:

or a pharmaceutically acceptable salt thereof, wherein:

R^(1A) is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, 3-10 memberedheterocyclyl, or 6-membered aryl, wherein the cycloalkyl, heterocyclyl,and aryl are optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, cyano,—N(R⁵)₂, —C(O)—(C₁-C₆ alkyl), —N(R⁵)C(O)—(C₁-C₆ alkyl), and —C(O)N(R⁵)₂;

R^(1B) represents independently for each occurrence C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, —(C₁-C₄alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄ alkylene)-O—(C₃-C₆ cycloalkyl), 3-6membered heterocyclyl, 6-membered aryl, cyano, or —N(R⁵)₂;

R² is hydrogen, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,C₁-C₆ alkoxy, —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄alkylene)-O—(C₃-C₆ cycloalkyl), 3-6 membered heterocyclyl, 6-memberedaryl, cyano, or —N(R⁵)₂;

R³ is hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;

R⁴ is one of the following:

-   -   C₃-C₈ cycloalkyl, 3-8 membered heterocycloalkyl, 9-13 membered        spiroheterocycloalkyl, —(C₂-C₆ alkylene)-O-phenyl, phenyl,        heteroaryl, a partially unsaturated 9-10 membered bicyclic        carbocyclyl, or a partially unsaturated 8-10 membered bicyclic        heterocyclyl; each of which is optionally substituted by 1, 2,        or 3 substituents independently selected from the group        consisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆        cycloalkyl, —(C₁-C₆ alkylene)-(C₃-C₆ cycloalkyl), hydroxyl,        C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), C₂-C₄ alkynyl, —(C₂-C₄        alkynyl)-C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), aryl, —O-aryl,        heteroaryl, saturated 3-8 membered heterocyclyl, amino, and        —CO₂R⁵; or    -   C₁₋₆ alkyl or C₂₋₆ alkynyl;

R⁵ represents independently for each occurrence hydrogen, C₁-C₆ alkyl,or C₃-C₆ cycloalkyl; or two occurrences of R⁵ attached to the samenitrogen atom are taken together with the nitrogen atom to which theyare attached to form a 3-8 membered heterocyclic ring;

Y is a bond, —C(O)—, C₁-C₆ haloalkylene, C₃-C₆ cycloalkylene, or C₁-C₆alkylene optionally substituted with C₃-C₆ cycloalkylene;

Z is N or C(R²); and

n is 0, 1, or 2.

Definitions of the variables in Formula V above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii).

Accordingly, in certain embodiments, R^(1A) is C₁-C₃ alkyl, 3-6 memberedheterocyclyl, or 6-membered aryl, wherein the heterocyclyl and aryl areoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy. In certainembodiments, R^(1B) is C₁-C₃ alkyl or halogen.

In certain embodiments, R² is hydrogen.

In certain embodiments, R³ is hydrogen.

In certain embodiments, Y is C₁-C₆ alkylene. In certain embodiments, Yis C₁-C₆ haloalkylene.

In certain embodiments, R⁴ is C₃-C₈ cycloalkyl optionally substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl,C₁-C₆ alkoxy, C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy. Incertain embodiments, R⁴ is a partially unsaturated 9-10 memberedbicyclic carbocyclyl optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, heteroaryl, andsaturated 3-8 membered heterocyclyl. In certain embodiments, R⁴ is apartially unsaturated 9-10 membered bicyclic carbocyclyl optionallysubstituted by C₁-C₈ alkyl. In certain embodiments, R⁴ is phenylsubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, hydroxyl, C₁-C₆ alkoxy, C₂-C₄ alkynyl, —(C₂-C₄alkynyl)-C₁-C₆ alkoxy, 5-membered heteroaryl, and saturated 3-8 memberedheterocyclyl. In certain embodiments, R⁴ is phenyl substituted by 1, 2,or 3 substituents independently selected from the group consisting ofC₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆alkoxy, C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy.

In certain embodiments, n is 1.

The description above describes multiple embodiments relating tocompounds of Formula V. The patent application specifically contemplatesall combinations of the embodiments.

Another aspect of the invention provides substitutedfuro[3,2-b]pyridine-3-carboxamide and related compounds. The substitutedfuro[3,2-b]pyridine-3-carboxamide and related compounds are contemplatedto be useful in the methods, compositions, and kits described herein. Incertain embodiments, the substituted furo[3,2-b]pyridine-3-carboxamideor related compound is a compound embraced by Formula VI:

or a pharmaceutically acceptable salt thereof, wherein:

R^(1A) is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, 3-10 memberedheterocyclyl, or 6-membered aryl, wherein the cycloalkyl, heterocyclyl,and aryl are optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, cyano,—N(R⁵)₂, —C(O)—(C₁-C₆ alkyl), —N(R⁵)C(O)—(C₁-C₆ alkyl), and —C(O)N(R⁵)₂;

R^(1B) represents independently for each occurrence C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, —(C₁-C₄alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄ alkylene)-O—(C₃-C₆ cycloalkyl), 3-6membered heterocyclyl, 6-membered aryl, cyano, or —N(R⁵)₂;

R² is hydrogen, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,C₁-C₆ alkoxy, —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄alkylene)-O—(C₃-C₆ cycloalkyl), 3-6 membered heterocyclyl, 6-memberedaryl, cyano, or —N(R⁵)₂;

R³ is hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;

R⁴ is one of the following:

-   -   C₃-C₈ cycloalkyl, 3-8 membered heterocycloalkyl, 9-13 membered        spiroheterocycloalkyl, —(C₂-C₆ alkylene)-O-phenyl, phenyl,        heteroaryl, a partially unsaturated 9-10 membered bicyclic        carbocyclyl, or a partially unsaturated 8-10 membered bicyclic        heterocyclyl; each of which is optionally substituted by 1, 2,        or 3 substituents independently selected from the group        consisting of C₁—C alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆        cycloalkyl, —(C₁-C₆ alkylene)-(C₃-C₆ cycloalkyl), hydroxyl,        C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), C₂-C₄ alkynyl, —(C₂-C₄        alkynyl)-C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), aryl, —O-aryl,        heteroaryl, saturated 3-8 membered heterocyclyl, amino, and        —CO₂R⁵; or    -   C₁-C₆ alkyl or C₂₋₆ alkynyl;

R⁵ represents independently for each occurrence hydrogen, C₁-C₆ alkyl,or C₃-C₆ cycloalkyl; or two occurrences of R⁵ attached to the samenitrogen atom are taken together with the nitrogen atom to which theyare attached to form a 3-8 membered heterocyclic ring;

Y is a bond, —C(O)—, C₁-C₆ haloalkylene, C₃-C₆ cycloalkylene, or C₁-C₆alkylene optionally substituted with C₃-C₆ cycloalkylene;

Z is N or C(R²); and

n is 0, 1, or 2.

Definitions of the variables in Formula VI above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii).

Accordingly, in certain embodiments, R^(1A) is C₁-C₃ alkyl, 3-6 memberedheterocyclyl, or 6-membered aryl, wherein the heterocyclyl and aryl areoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, and C₁-C₆ alkoxy. In certainembodiments, R^(1B) is C₁-C₃ alkyl or halogen. In certain embodimentsR^(1A) is C₁-C₃ alkyl.

In certain embodiments, R^(1B) is C₁-C₃ alkyl or halogen.

In certain embodiments, R² is hydrogen. In certain embodiments, R³ ishydrogen. In yet other embodiments, R² and R³ are hydrogen.

In certain embodiments, Y is a bond. In certain embodiments, Y is C₁-C₆alkylene. In certain embodiments, Y is C₁-C₆ haloalkylene. In yet otherembodiments, Y is a bond or C₁-C₆ alkylene.

In certain embodiments, R⁴ is C₃-C₈ cycloalkyl optionally substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl,C₁-C₆ alkoxy, C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy. Incertain embodiments, R⁴ is a partially unsaturated 9-10 memberedbicyclic carbocyclyl optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆ alkoxy,C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, heteroaryl, andsaturated 3-8 membered heterocyclyl. In certain embodiments, R⁴ is apartially unsaturated 9-10 membered bicyclic carbocyclyl optionallysubstituted by C₁-C₆ alkyl. In certain embodiments, R⁴ is phenylsubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, hydroxyl, C₁-C₆ alkoxy, C₂-C₄ alkynyl, —(C₂-C₄alkynyl)-C₁-C₆ alkoxy, 5-membered heteroaryl, and saturated 3-8 memberedheterocyclyl. In certain embodiments, R⁴ is phenyl substituted by 1, 2,or 3 substituents independently selected from the group consisting ofC₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆alkoxy, C₂-C₄ alkynyl, and —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy. In yet otherembodiments, R⁴ is C₃-C₈ cycloalkyl, phenyl, or a partially unsaturated9-10 membered bicyclic carbocyclyl; each of which is optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, —(C₁-C₆ alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, and C₁-C₆alkoxy.

In certain embodiments, n is 1.

In yet other embodiments, R^(A) is C₁-C₃ alkyl, R^(1B) is C₁-C₃ alkyl orhalogen, and n is 1.

The description above describes multiple embodiments relating tocompounds of Formula VI. The patent application specificallycontemplates all combinations of the embodiments.

Another aspect of the invention provides compounds of Formula VII, whichare contemplated to be useful in the methods, compositions, and kitsdescribed herein:

or a pharmaceutically acceptable salt thereof, wherein:

R^(1A) is a 3-10 membered oxoheterocyclyl optionally substituted with 1,2, or 3 substituents independently selected from the group consisting ofhalogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆alkoxy, cyano, —N(R⁵)₂, —C(O)—(C₁-C₆ alkyl), —N(R⁵)C(O)—(C₁-C₆ alkyl),and —C(O)N(R⁵)₂;

R^(1B) represents independently for each occurrence C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, —(C₁-C₄alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄ alkylene)-O—(C₃-C₆ cycloalkyl), 3-6membered heterocyclyl, 6-membered aryl, cyano, or —N(R⁵)₂; R² ishydrogen, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆alkoxy, —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄ alkylene)-O—(C₁-C₆cycloalkyl), 3-6 membered heterocyclyl, 6-membered aryl, cyano, or—N(R⁵)₂;

R³ is hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;

R⁴ is one of the following:

-   -   C₃-C₈ cycloalkyl, 3-8 membered heterocycloalkyl, 9-13 membered        spiroheterocycloalkyl, —(C₂-C₆ alkylene)-O-phenyl, phenyl,        heteroaryl, a partially unsaturated 9-10 membered bicyclic        carbocyclyl, or a partially unsaturated 8-10 membered bicyclic        heterocyclyl; each of which is optionally substituted by 1, 2,        or 3 substituents independently selected from the group        consisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆        cycloalkyl, —(C₁-C₆ alkylene)-(C₃-C₆ cycloalkyl), hydroxyl,        C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), C₂-C₄ alkynyl, —(C₂-C₄        alkynyl)-C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), aryl, —O-aryl,        heteroaryl, saturated 3-8 membered heterocyclyl, amino, and        —CO₂R⁵; or    -   C₁₋₆ alkyl or C₂₋₆ alkynyl;

R⁵ represents independently for each occurrence hydrogen, C₁-C₆ alkyl,or C₁-C₆ cycloalkyl; or two occurrences of R⁵ attached to the samenitrogen atom are taken together with the nitrogen atom to which theyare attached to form a 3-8 membered heterocyclic ring;

Y is a bond, —C(O)—, C₁-C₆ haloalkylene, C₃-C₆ cycloalkylene, or C₁-C₆alkylene optionally substituted with C₃-C₆ cycloalkylene;

Z¹ and Z² are as follows:

-   -   (i) Z¹ is C(R²), and then Z² is N; or    -   (ii) Z¹ is N, and then Z² is C(R²); and

n is 0, 1, or 2.

Definitions of the variables in Formula VII above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii).Accordingly, in certain embodiments, R^(1B) is C₁-C₃ alkyl.

In certain embodiments, Z¹ is C(R²), and then Z² is N. In certain otherembodiments, Z¹ is N, and then Z² is C(R²). In certain embodiments, n is0, 1, or 2. In certain embodiments, R² and R³ are hydrogen. In certainembodiments, Y is a bond or C₁-C₆ alkylene. In certain embodiments, Y isC₁-C₆ haloalkylene. In certain embodiments, R⁴ is C₃-C₈ cycloalkyl,phenyl, or a partially unsaturated 9-10 membered bicyclic carbocyclyl;each of which is optionally substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₈ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —(C₁-C₆ alkylene)-(C₃-C₆cycloalkyl), hydroxyl, and C₁-C₆ alkoxy.

In certain other embodiments, the compound is one of the compoundslisted in Table 1 or 2 below or a pharmaceutically acceptable saltthereof. In certain embodiments, the compound is one of the compoundslisted in Table 3 herein or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is one of the compounds listed inTable 1, 2, or 3 herein or a pharmaceutically acceptable salt thereof.In certain other embodiments, the compound is6-(2-cyano-4-fluorophenyl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamideor a pharmaceutically acceptable salt thereof. In certain otherembodiments, the compound is6-(2-cyano-4-fluorophenyl)-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamideor a pharmaceutically acceptable salt thereof. In certain embodiments,the compound is one of the compounds listed in Table 4 herein or apharmaceutically acceptable salt thereof

TABLE 1

Compound No. R^(1A) R^(1B) R^(1C) W X Y R4 I-1 Cl H H N CH a bond

I-2 —CH₃ H —CH₃ CH N a bond

I-3 Cl —CH₃ H N CH a bond

I-4 Cl H H N CH a bond

I-5 Cl H H N CH a bond

I-6 Cl H H N CH a bond

I-7 —CH₃ H —CH₃ N CH a bond

I-8 —CH₃ H —CH₃ N CH a bond

I-9 —CH₃ H —CH₃ N CH a bond

I-10 —CH₃ H —CH₃ N CH a bond

I-11 —CH₃ H —CH₃ N CH a bond

I-12 Cl H —CH₃ N CH a bond

I-13 Cl H —CH₃ N CH a bond

I-14 Cl —CH₃ H N CH a bond

I-15 —CH₃ H —CH₃ CH N a bond

I-16 —CH₃ H —CH₃ CH N a bond

I-17 —CH₃ H —CH₃ CH N a bond

I-18 Cl —CH₃ H N CH C₁—C₄ alkylene

I-19 Cl H H N CH C₁—C₄ alkylene

I-20 —CH₃ H —CH₃ N CH C₁—C₄ alkylene

I-21 Cl H —CH₃ N CH C₁—C₄ alkylene

I-22 Cl H —CH₃ CH N C₁—C₄ alkylene

I-23 —CH₃ H —CH₃ N CH C₁—C₄ alkylene

I-24 Cl H —CH₃ N CH C₁—C₄ alkylene

I-25 Cl H —CH₃ CH N C₁—C₄ alkylene

I-26 —CH₃ H —CH₃ N CH C₁—C₄ alkylene

TABLE 2 Compound No. Compound Structure II-1

II-2

II-3

II-4

II-5

II-6

II-7

II-8

II-9

II-10

II-11

II-12

II-13

II-14

II-15

II-16

II-17

II-18

II-19

II-20

II-21

II-22

II-23

II-24

II-25

II-26

II-27

II-28

Methods for preparing exemplary substitutedimidazo[1,2-b]pyridazine-3-carboxamide and related compounds describedherein are illustrated in the following synthetic scheme. These schemeis provided for the purpose of illustrating the invention, and shouldnot be regarded in any manner as limiting the scope or the spirit of theinvention. Starting materials shown in the scheme can be obtained fromcommercial sources or can be prepared based on procedures described inthe literature.

The synthetic route illustrated in Scheme 1 depicts an exemplaryprocedure for preparing substitutedimidazo[1,5-b]pyridazine-7-carboxamide compounds. In the first step,Pd-catalyzed cross-coupling of 3,6-dichloro-4-methylpyridazine(R^(i)=Me, R^(ii)=H) A with a variety of aryl or heteroaryl boronicacids, halides or trialkylstannyl reagents may be accomplished usingstandard cross-coupling procedures (such as Pd(dppf)₂Cl₂.CH₂Cl₂ in DMEin the presence of K₃PO₄) to afford the substituted pyrimidinyl chlorideB. A second Pd-catalyzed cross-coupling reaction of the pyrimidinylchloride B and ZnCl₂ affords the corresponding nitrile, which is reducedto give amine C. Coupling of amine C with ethyl 2-chloro-2-oxoacetate inthe presence of Et₃N affords the an amido ester which undergoes anintramolecular condensation in the presence of POCl₃ to afford theimidazo[1,5,b]pyrimidine ester. Hydrolysis of the carboxylic ester underbasic or neutral conditions affords carboxylic acid D. In the finalstep, coupling of carboxylic acid D with a variety of substitutedaromatic or aliphatic amines may be accomplished using standard peptidecoupling procedures (such as HATU and/or HOBT in DMF in the presence ofDIPEA) to afford carboxamide E.

The synthetic route illustrated in Scheme 2 depicts an alternativeexemplary procedure for preparing substitutedimidazo[1,2-b]pyridazine-3-carboxamide compounds. In the first step,substitution of pyrimidinyl chloride B with hydrazine followed byRaney-Ni catalyzed hydrogenation affords amine F. Condensation of amineF with dimethyl acetamide affords an imine which undergoes animine-enolate condensation with the enolate of ethyl 2-bromo acetatefollowed by an intramolecular condensation to afford theimidazo[1,2,b]pyrimidine ester. Hydrolysis of the carboxylic ester underbasic or neutral conditions affords carboxylic acid G. In the finalstep, coupling of carboxylic acid G with a variety of substitutedaromatic or aliphatic amines may be accomplished using standard peptidecoupling procedures (such as HATU and/or HOBT in DMF in the presence ofDIPEA) to afford carboxamide H.

The synthetic route illustrated in Scheme 3 depicts an exemplaryprocedure for preparing substitutedtriazolo[4,3-b]pyridazine-3-carboxamide compounds. In the first step,substitution of pyrimidinyl chloride B with hydrazine followed bycoupling with ethyl chloro oxalyl and subsequent intramolecularcondensation affords triazolo[4,3,b]pyrimidine ester I. In the finalstep, coupling of carboxylic ester I with a variety of substitutedaromatic or aliphatic amines may be accomplished via Weinreb's amide toafford carboxamide J.

The synthetic route illustrated in Scheme 4 depicts an exemplaryprocedure for preparing substitutedisothiazolo[4,5-b]pyridine-3-carboxamide compounds. In the first step,condensation of methyl 4-aminoisothiazole-3-carboxylate K with4-methyleneoxetan-2-one affords the corresponding amido carboxylatewhich undergoes an intramolecular condensation in the presence of PPA toafford the corresponding bicyclic hydroxyl which is transformed tochloro-bicyclo carboxylate L. In the second step, Pd-catalyzedcross-coupling of chloride L with a variety of aryl or heteroarylboronic acids, halides or trialkylstannyl reagents may be accomplishedusing standard cross coupling procedures (such as Pd(dppf)₂Cl₂.CH₂Cl₂ inDME in the presence of K₃PO₄) to afford substitutedisothiazolo[4,5-b]pyridinyl carboxylic ester M. Hydrolysis of thecarboxylic ester under basic or neutral conditions affords carboxylicacid N. In the final step, coupling of carboxylic acid N with a varietyof substituted aromatic or aliphatic amines may be accomplished usingstandard peptide coupling procedures (such as HATU and/or HOBT in DMF inthe presence of DIPEA) to afford carboxamide O.

The synthetic scheme illustrated in Scheme 5 illustrates an exemplaryprocedure for preparing substituted thieno[3,2-b]pyridine-3-carboxamidecompounds. In the first step condensation of thiophen-3-amine P withpentane-2,4-dione (R^(i)=R^(iii)=Me, R^(ii)=H) in the presence of H₃PO₄affords 5,7-dimethylthieno[3,2-b]pyridine Q. Bromination of bicycliccompound Q followed by Pd(0)-catalysed coupling in methanol to installthe methyl carboxylate, followed by hydrolysis affords carboxylic acidR. In the final step, coupling of carboxylic acid R with a variety ofsubstituted aromatic or aliphatic amines may be accomplished usingstandard peptide coupling procedures (such as HATU and/or HOBT in DMF inthe presence of DIPEA) to afford carboxamide S.

The reaction procedures in Schemes 1-5 are contemplated to be amenableto preparing a wide variety of carboxamide compounds having differentsubstituents at variable R. Furthermore, if a functional group that ispart of variable R would not be amenable to a reaction conditiondescribed in Schemes 1-5, it is contemplated that the functional groupcan first be protected using standard protecting group chemistry andstrategies, and then the protecting group is removed after completingthe desired synthetic transformation. See, for example, Greene, T. W.;Wuts, P. G. M. Protective Groups in Organic Synthesis, 2^(nd) ed.;Wiley: New York, 1991, for further description of protecting chemistryand strategies. In certain other embodiments, a functional group insubstituent R can converted to another functional group using standardfunctional group manipulation procedures known in the art. See, forexample, “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming,eds., 1991-1992).

Substituted imidazo[1,5-b]pyridazine compounds described herein may beprepared by synthetic methodology analogous to that described above forthe substituted imidazo[1,2-b]pyridazine compounds.

III. Therapeutic Applications

The invention provides methods of treating medical disorders, such asGaucher disease, Parkinson's disease, Lewy body disease, dementia,multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, ananxiety disorder, major depression, polycystic kidney disease, type 2diabetes, open angle glaucoma, multiple sclerosis, endometriosis, andmultiple myeloma, using the substituted imidazo[1,2-b]pyridazinecompounds, substituted imidazo[1,5-b]pyridazine compounds, relatedcompounds, and pharmaceutical compositions described herein. Treatmentmethods include the use of a substituted imidazo[1,2-b]pyridazinecompound, substituted imidazo[1,5-b]pyridazine compound, or relatedcompound described herein as a stand-alone therapeutic agent and/or aspart of a combination therapy with another therapeutic agent. Althoughnot wishing to be bound by a particular theory, it is understood thatsubstituted imidazo[1,2-b]pyridazine compounds, substitutedimidazo[1,5-b]pyridazine compounds, and related compounds describedherein may activate glucocerebrosidase (Gcase).

Methods of Treating Medical Disorders

One aspect of the invention provides a method of treating a disorderselected from the group consisting of Gaucher disease, Parkinson'sdisease, Lewy body disease, dementia, multiple system atrophy, epilepsy,bipolar disorder, schizophrenia, an anxiety disorder, major depression,polycystic kidney disease, type 2 diabetes, open angle glaucoma,multiple sclerosis, endometriosis, and multiple myeloma. The methodcomprises administering to a patient in need thereof a therapeuticallyeffective amount of a substituted imidazo[1,2-b]pyridazine compound,substituted imidazo[1,5-b]pyridazine compound, or related compounddescribed herein to treat the disorder. The compound may be a compoundof Formula I, which, as described above in Section II, is representedby:

or a pharmaceutically acceptable salt thereof, wherein:

R^(1A) is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, 3-10 memberedheterocyclyl, or 6-membered aryl, wherein the cycloalkyl, heterocyclyl,and aryl are optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, cyano,—N(R⁵)₂, —C(O)—(C₁-C₆ alkyl), —N(R⁵)C(O)—(C₁-C₈ alkyl), and —C(O)N(R⁵)₂;

R^(1B) represents independently for each occurrence C₁-C₆ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, —(C₁-C₄alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄ alkylene)-O—(C₃-C₆ cycloalkyl), 3-6membered heterocyclyl, 6-membered aryl, cyano, or —N(R⁵)₂;

R² is hydrogen, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,C₁-C₆ alkoxy, —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄alkylene)-O—(C₃-C₆ cycloalkyl), 3-6 membered heterocyclyl, 6-memberedaryl, cyano, or —N(R⁵)₂;

R³ is hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;

R⁴ is one of the following:

-   -   C₃-C₈ cycloalkyl, 3-8 membered heterocycloalkyl, 9-13 membered        spiroheterocycloalkyl, —(C₂-C₆ alkylene)-O-phenyl, phenyl,        heteroaryl, a partially unsaturated 9-10 membered bicyclic        carbocyclyl, or a partially unsaturated 8-10 membered bicyclic        heterocyclyl; each of which is optionally substituted by 1, 2,        or 3 substituents independently selected from the group        consisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆        cycloalkyl, —(C₁-C₆ alkylene,)-(C₃-C₆ cycloalkyl), hydroxyl,        C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), C₂-C₄ alkynyl, —(C₂-C₄        alkynyl)-C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), aryl, —O-aryl,        heteroaryl, saturated 3-8 membered heterocyclyl, amino, and        —CO₂R⁵; or    -   C₁₋₆ alkyl or C₂₋₆ alkynyl;

R⁵ represents independently for each occurrence hydrogen, C₁-C₆ alkyl,or C₃-C₆ cycloalkyl; or two occurrences of R⁵ attached to the samenitrogen atom are taken together with the nitrogen atom to which theyare attached to form a 3-8 membered heterocyclic ring; Y is a bond,—C(O)—, C₁-C₆ haloalkylene, C₃-C₆ cycloalkylene, or C₁-C₆ alkyleneoptionally substituted with C₃-C₆ cycloalkylene; and

n is 0, 1, or 2;

provided that when Y—R⁴ is —CH₂-phenyl, then n is 1 or 2.

In yet other embodiments, the compound is a compound of Formula II, asset forth in Section II above. In still other embodiments, the compoundis a compound of Formula I-A, as set forth in Section II above. In yetother embodiments, the compound is a compound of Formula III, as setforth in Section II above.

In certain embodiments, the disorder is Gaucher disease, Parkinson'sdisease, Lewy body disease, dementia, or multiple system atrophy. Incertain other embodiments, the disorder is Gaucher disease. In certainembodiments, the disorder is Parkinson's disease. In certainembodiments, the disorder is Lewy body disease. In certain embodiments,the disorder is dementia. In certain embodiments, the disorder is adementia selected from the group consisting of Alzheimer's disease,frontotemporal dementia, and a Lewy body variant of Alzheimer's disease.In certain embodiments, the disorder is multiple system atrophy.

In certain embodiments, the disorder is an anxiety disorder, such aspanic disorder, social anxiety disorder, or generalized anxietydisorder.

Efficacy of the compounds in treating Gaucher disease, Parkinson'sdisease, Lewy body disease, dementia, multiple system atrophy, epilepsy,bipolar disorder, schizophrenia, an anxiety disorder, major depression,polycystic kidney disease, type 2 diabetes, open angle glaucoma,multiple sclerosis, endometriosis, and multiple myeloma may be evaluatedby testing the compounds in assays known in the art for evaluatingefficacy against these diseases and/or, e.g., for activation ofglucocerebrosidase (Gcase), as discussed in the Examples below.

In certain embodiments, the patient is a human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Section II, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A, a compound of FormulaII, a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula II, a compound of FormulaIII, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula III.

The description above describes multiple embodiments relating to methodsof treating various disorders using certain substitutedimidazo[1,2-b]pyridazine compounds and substitutedimidazo[1,5-b]pyridazine compounds. The patent application specificallycontemplates all combinations of the embodiments. For example, theinvention contemplates methods for treating Gaucher disease, Parkinson'sdisease, Lewy body disease, dementia, or multiple system atrophy byadministering a therapeutically effective amount of a compound ofFormula I-A wherein R^(1A) and R^(1C) are C₁-C₆ alkyl, R² is hydrogen,and R⁴ is C₃-C₈ cycloalkyl or phenyl; each of which is optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl.

Medical Use and Preparation of Medicament

Another aspect of the invention relates to compounds and compositionsdescribed herein for use in treating a disorder described herein.Another aspect of the invention pertains to use of a compound orcomposition described herein in the preparation of a medicament fortreating a disorder described herein.

Combination Therapy

The invention embraces combination therapy, which includes theadministration of a substituted imidazo[1,2-b]pyridazine compound,substituted imidazo[1,5-b]pyridazine compound, or related compounddescribed herein (such as compound of Formula I, I-A, II, III, IV, V,VI, or VII) and a second agent as part of a specific treatment regimenintended to provide the beneficial effect from the co-action of thesetherapeutic agents. The beneficial effect of the combination may includepharmacokinetic or pharmacodynamic co-action resulting from thecombination of therapeutic agents.

Exemplary second agents for use in treating Gaucher disease include, forexample, taliglucerase alfa, velaglucerase alfa, eliglustat, andmiglustat. Exemplary second agents for use in treating Parkinson'sdisease include, for example, a glucosylceramide synthase inhibitor(e.g., ibiglustat), an acid ceramidase inhibitor (e.g., carmofur), anacid shingomyelinase activator, or salt thereof. Additionalglucosylceramide synthase inhibitors for use in combination therapiesinclude, for example, those described in International PatentApplication Publications WO 2015/089067, WO 2014/151291, WO 2014/043068,WO 2008/150486, WO 2010/014554, WO 2012/129084, WO 2011/133915, and WO2010/091164; U.S. Pat. Nos. U.S. Pat. Nos. 9,126,993, 8,961,959,8,940,776, 8,729,075, and 8,309,593; and U.S. Patent ApplicationPublications US 2014/0255381 and US 2014/0336174; each of which arehereby incorporated by reference. Additional acid ceramidase inhibitorsfor use in combination therapies include, for example, those describedin International Patent Application Publications WO 2015/173168 and WO2015/173169, each of which are hereby incorporated by reference.

IV. Pharmaceutical Compositions

The invention provides pharmaceutical compositions comprising asubstituted imidazo[1,2-b]pyridazine compound, substitutedimidazo[1,5-b]pyridazine compound, or related compound described herein,such as a compound of Formula I, I-A, II, III, IV, V, VI, or VII. Incertain embodiments, the pharmaceutical compositions preferably comprisea therapeutically-effective amount of one or more of the substitutedimidazo[1,2-b]pyridazine compounds described above, formulated togetherwith one or more pharmaceutically acceptable carriers. As described indetail below, the pharmaceutical compositions of the present inventionmay be specially formulated for administration in solid or liquid form,including those adapted for the following: (1) oral administration, forexample, drenches (aqueous or non-aqueous solutions or suspensions),tablets (e.g., those targeted for buccal, sublingual, and/or systemicabsorption), boluses, powders, granules, pastes for application to thetongue; (2) parenteral administration by, for example, subcutaneous,intramuscular, intravenous or epidural injection as, for example, asterile solution or suspension, or sustained-release formulation; (3)topical application, for example, as a cream, ointment, or acontrolled-release patch or spray applied to the skin; (4)intravaginally or intrarectally, for example, as a pessary, cream orfoam; (5) sublingually; (6) jocularly; (7) transdermally; or (8)nasally.

The phrase “therapeutically-effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect in at least a sub-population of cells in an animal ata reasonable benefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration.

The amount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will generally be that amountof the compound which produces a therapeutic effect. Generally, out ofone hundred percent, this amount will range from about 0.1 percent toabout ninety-nine percent of active ingredient, preferably from about 5percent to about 70 percent, most preferably from about 10 percent toabout 30 percent.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,celluloses, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present invention. In certain embodiments, an aforementionedformulation renders orally bioavailable a compound of the presentinvention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds and surfactants, such as poloxamer and sodium laurylsulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, zinc stearate, sodium stearate, stearic acid, and mixturesthereof; (10) coloring agents; and (11) controlled release agents suchas crospovidone or ethyl cellulose. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-shelled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99% (morepreferably, 10 to 30%) of active ingredient in combination with apharmaceutically acceptable carrier.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administrations are preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Preferably, the compounds areadministered at about 0.01 mg/kg to about 200 mg/kg, more preferably atabout 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5mg/kg to about 50 mg/kg. When the compounds described herein areco-administered with another agent (e.g., as sensitizing agents), theeffective amount may be less than when the agent is used alone.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. Preferred dosing is one administrationper day.

V. Kits for Use in Medical Applications

Another aspect of the invention provides a kit for treating a disorder.The kit comprises: i) instructions for treating a medical disorder, suchas Gaucher disease, Parkinson's disease, Lewy body disease, dementia, ormultiple system atrophy; and ii) a substituted imidazo[1,2-b]pyridazinecompound or substituted imidazo[1,5-b]pyridazine compound describedherein, such as a compound of Formula I, I-A, II, III, IV, V, VI, orVII. The kit may comprise one or more unit dosage forms containing anamount of a substituted imidazo[1,2-b]pyridazine compound, substitutedimidazo[1,5-b]pyridazine compound, or related compound described herein,such as a compound of Formula I, I-A, II, III, IV, V, VI, or VII that iseffective for treating said medical disorder, e.g., Gaucher disease,Parkinson's disease, Lewy body disease, dementia, or multiple systematrophy.

The description above describes multiple aspects and embodiments of theinvention, including substituted imidazo[1,2-b]pyridazine compounds,substituted imidazo[1,5-b]pyridazine compounds, compositions comprisinga substituted imidazo[1,2-b]pyridazine compound or substitutedimidazo[1,5-b]pyridazine compound, methods of using the substitutedimidazo[1,2-b]pyridazine compounds, substituted imidazo[1,5-b]pyridazinecompounds, and related compounds, and kits. The patent applicationspecifically contemplates all combinations and permutations of theaspects and embodiments. For example, the invention contemplatestreating Gaucher disease, Parkinson's disease, Lewy body disease,dementia, or multiple system atrophy in a human patient by administeringa therapeutically effective amount of a compound of Formula I-A.Further, for example, the invention contemplates a kit for treatingGaucher disease, Parkinson's disease, Lewy body disease, dementia, ormultiple system atrophy, the kit comprising (i) instructions fortreating Gaucher disease, Parkinson's disease, Lewy body disease,dementia, or multiple system atrophy and (ii) a substitutedimidazo[1,2-b]pyridazine compound described herein, such as a compoundof Formula I-A.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.Standard abbreviations have been used in the Examples in certaininstances, such as the abbreviation “RT” for room temperature, and theabbreviation “h” for hours.

Example 1—Preparation of Compounds

Substituted imidazo[1,2-b]pyridazine compounds, substitutedimidazo[1,5-b]pyridazine compounds, related compounds were preparedbased on general procedures described in Part I below. Exemplaryprocedures for preparing specific carboxylic acid compounds useful assynthetic intermediates in the preparation of certain substitutedimidazo[1,2-b]pyridazine compounds, substituted imidazo[1,5-b]pyridazinecompounds, and/or related compounds are provided in Part II below.Specific substituted imidazo[1,2-b]pyridazine compounds, substitutedimidazo[1,5-b]pyridazine compounds, and related compounds preparedaccording to the general procedures are provided in Part III below.

Part I—General Procedures

General Procedure A: Preparation of Amide by Coupling of a CarboxylicAcid Compound with an Amine Compound

To a stirred solution of carboxylic acid compound (1.0 equivalent), HATU(1.5 equivalents), and DIPEA (3.75 equivalents) in DCM or DMF (˜4 mL/0.2mmol) is added amine compound (1.25-2.0 equivalents). The reactionmixture is stirred at room temperature for 4-16 hours, and then washedwith saturated aqueous NaHCO₃ solution (5 mL/0.2 mmol), aqueous citricacid solution (5 mL/0.2 mmol) and brine (5 mL/0.2 mmol). The combinedextracts are dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The resulting crude material is purified by silica gel columnchromatography or preparatory HPLC to give the amide compound.

General Procedure B: Conversion of Carboxylic Ester Compound toCarboxylic Acid Compound

To a solution of carboxylic ester (1.0 equivalent) in EtOH (5.0 mL/1.0mmol) and water (0-3.0 mL/1.0 mmol) is added NaOH (2.0-5.0 equivalents)and the mixture is heated at 80° C. for 2 hours and then concentrated.To the concentrate, 6N HCl solution is added to adjust the pH to 5˜6 andthen the mixture is stirred for 10 minutes and subsequently filtered.The resulting solid is collected and dried to give the carboxylic acidcompound.

General Procedure C: Preparation of Coupled Aryl and Heteroaryl GroupsUsing Suzuki Catalyzed Coupling Conditions Between an Organoboronic Acidor Ester and an Aryl Halide or Heteroaryl Halide

A suspension of heteroaryl chloride (1 equivalent), organoboronic acidor organoboronic ester (1.2 equivalents), K₃PO₄ (3.0 equivalents) andPd(dppf)Cl₂.DCM (5 mol %) or Pd₂(dba)₃ (10 mol %) in DME or 1,4-dioxane(40 mL/mmol) is stirred at 70-100° C. for 2-6 hours under N₂. Then, thereaction mixture is quenched with water (30 mL/mmol) and resultingmixture extracted with EtOAc (30 mL/mmol×3). The organic phases arewashed with water (30 mL/mmol) and brine (30 mL/mmol), dried overanhydrous Na₂SO₄ and filtered. The filtrate is concentrated in vacuo,and the resulting residue is purified by silica gel columnchromatography to afford the coupled ring system.

General Procedure D: Preparation of Coupled Aryl and Heteroaryl GroupsUsing Buchwald Catalyzed Coupling Conditions Between an Organohalide andOrganotin Reagent

A solution of organochloride (1.0 equivalent) and organotin reagent (1.0equivalent) in 1,4-dioxane (20 mL/mmol) is stirred and purged with N₂three times at RT. Then Pd(dppf)Cl₂.DCM (10 mol %) is quickly addedunder a N₂ atmosphere to the reaction mixture, followed by additionalpurging with N₂ (×3) and the resulting mixture is stirred at 120° C. forovernight. Next, the reaction mixture is cooled to RT and then quenchedwith water (20 mL/mmol). The resulting mixture is extracted with EA (20mL/mmol×3), and the organic phases are dried over anhydrous Na₂SO₄ andfiltered and concentrated in vacuo. The resulting residue is purified bysilica gel column chromatography or preparative-TLC to afford thecoupled ring system.

General Procedure E: Preparation of Heteroaryl Nitriles Using PdCatalyzed Cross Coupling Between an Organohalide and Dicyanozinc.

A solution of organohalide (1.0 equivalent), Pd₂(dba)₃ (5 mol %), dppf(10 mol %), and Zn(CN)₂ (2.0 equivalents) in DMF (5 mL/mmol) is stirredat 120° C. under N₂ overnight, then cooled to RT and filtered. Thefiltrate is concentrated in vacuo and the residue is purified by columnchromatography on silica gel to afford the heteroaryl nitrile.

General Procedure F: Preparation of Heteroaryl Amines UsingHydrogenation of Nitriles

A suspension of heteroaryl nitrile (1.0 equivalent) and 10% Pd/C (25mg/mmol) in MeOH (5 mL/mmol) in the presence of 6N HCl (1.25 mL/mmol) isstirred at RT for 12 h under a H₂ atmosphere. The reaction mixture isfiltered through celite and washed with MeOH (5 mL/mmol). The filtrateis concentrated in vacuo to afford the heteroaryl amine as the HCl salt.This is used in the next step without purification.

General Procedure G: Preparation of Pyrimidino Amido Ester Using AminoCoupling of Ethyl Oxalyl Chloride

To a solution of amine hydrochloride (1.0 equivalent) in DCM (4 mL/mmol)is added Et₃N (4.0 equivalents), followed by the addition of ethyl2-chloro-2-oxoacetate (1.5 equivalents). The reaction mixture is stirredfor 2 hours, diluted with DCM (8 mL/mmol), washed with brine (4mL/mmol), separated and dried over anhydrous Na₂SO₄ and filtered. Thefiltrate is concentrated in vacuo and the residue is purified by silicagel chromatography to afford the amido ester.

General Procedure H: Preparation of Imidazo[1,5-b]Pyridazines UsingIntramolecular Condensation of Pyrimidino Amido Ester

To a suspension of pyrimidino amido ester (1.0 equivalent) in1,2-dichloroethane (10 mL/mmol) was added POCl₃ (3.0 equivalents). Thereaction mixture is stirred at 70° C. for 24 h, then cooled to RT, andpoured into ice water (5 mL/mmol). The resulting mixture is separated,and the aqueous phase is extracted with DCM (5 mL/mmol×3). The combinedorganic phases are washed with saturated NaHCO₃ (10 mL/mmol) and brine(10 mL/mmol), dried over anhydrous Na₂SO₄ and filtered. The filtrate isconcentrated in vacuo, and the resulting residue is purified by silicagel chromatography to afford the imidazo[1,5-b]pyridazine.

Part II—Preparation of Specific Carboxylic Acid Compounds

Exemplary procedures for preparing specific carboxylic acid compoundsuseful in the preparation of certain substituted carboxamide compoundsare provided below.

6,8-Dimethylimidazo[1,2-b]pyridazine-3-carboxylic acid

To a solution of 4H-1,2,4-triazol-4-amine (5 g, 60 mmol) in anhydroustoluene (25 mL) was added 2,4-pentanedione (7.1 g, 60 mmol) and p-TsOH(1.0 g, 6.0 mmol) and the mixture was heated at reflux for 16 h in aDean Stark trap. Once the reaction was complete, the resulting yellow,transparent solution was cooled to RT and concentrated in vacuo. Theresulting crude oil was dissolved in DCM and washed with saturatedNaHCO₃ solution. The organic layer was isolated, dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated in vacuo and thecrude was purified by silica gel column chromatography (DCM/MeOH, 20:1v/v) to give 6,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine (7.0 g, 80%)as a yellow solid; LC-MS m/z: 149.1 [M+H]⁺.

To a solution of 6,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine (6.0 g,40.5 mmol) in nitromethane (35 mL) was added bromoacetophenone (8.1 g,40.5 mmol). The reaction mixture was heated at reflux under an inertatmosphere for 2.5 h. Then, the reaction mixture was allowed to cool andnext concentrated in vacuo to afford a red sticky oil, which waspurified by silica gel column chromatography (DCM/MeOH, 7:1 (v/v)) toafford6,8-dimethyl-2-(2-oxo-2-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazin-2-iumbromide (6.0 g, 75%) as orange crystals; LC-MS m/z: 268.1 [M+H]⁺.

A solution of6,8-dimethyl-2-(2-oxo-2-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazin-2-iumbromide (5.0 g, 14.4 mmol) in 20% aqueous NaOH solution (72.0 mmol) washeated at reflux for 16 h. Then, the reaction mixture was concentratedin vacuo and the residue was purified by silica gel columnchromatography (DCM/MeOH, 10:1 (v/v)) to afford4,6-dimethylpyridazin-3-amine (1.7 g, 96%) as a pale brown powder; LC-MSm/z: 124.1 [M+H]⁺.

To a suspension of 4,6-dimethylpyridazin-3-amine (1.23 g, 10.0 mmol) in10 mL of EtOH was added DIPEA (12.9 g, 100 mmol) and ethyl2-chloro-3-oxopropanoate (3.00 g, 20.0 mmol). The reaction mixture wasstirred at 75° C. for 16 h, cooled to RT, and concentrated in vacuo. Theresulting residue was partitioned between EtOAc and water, and theorganic layer was separated, washed with brine (20 mL), dried overMgSO₄, filtered, and concentrated in vacuo. The resulting residual brownsolid was purified on a silica gel flash chromatography column (EA/PE;1:1) to give ethyl 6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylate(300 mg, 14%) as a yellow solid. ¹H NMR (500 MHz, CDCl₃): δ 8.27 (s,1H), 9.40 (s, 1H), 4.47 (q, J=9.0 Hz, 2H), 2.66 (s, 6H), 1.45 (t, J=9.0Hz, 3H). LC-MS m/z: 220.1 [M+H]⁺

Following general procedure B, ethyl6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylate (180 mg, 0.82 mmol)afforded the tile compound (154 mg, 98%) as a yellow solid. LC-MS m/z:220.1 [M+H]⁺.

6-Chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid

To a solution of 3,6-dichloro-4-methylpyridazine (3.0 g, 18.4 mmol) inMeOH (20 mL) was added NH₃/MeOH (20 mL). The reaction mixture was heatedat 120° C. in a sealed tube for 12 h. Then, the reaction mixture wascooled to RT and concentrated in vacuo. The resulting residue wasrecrystallized in EtOH to give a mixture of6-chloro-4-methylpyridazin-3-amine and6-chloro-5-methylpyridazin-3-amine (2.4 g, 89%) as a yellow solid. LC-MSm/z: 144.1 [M+H]⁺.

A suspension of a mixture of 6-chloro-4-methylpyridazin-3-amine and6-chloro-5-methylpyridazin-3-amine (1.5 g, 10.5 mmol) in DMF-DMA (20 mL)was stirred at reflux for 5 h. The reaction mixture was concentrated invacuo to give a mixture of(E)-N-(6-chloro-5-methylpyridazin-3-yl)-N,N-dimethylformimidamide and(E)-N-(6-chloro-4-methylpyridazin-3-yl)-N,N-dimethylformimidamide, whichwas used directly in the next step. LC-MS m/z: 179.1 [M+H]⁺.

To a mixture of(E)-N-(6-chloro-5-methylpyridazin-3-yl)-N,N-dimethylformimidamide and(E)-N-(6-chloro-4-methylpyridazin-3-yl)-N,N-dimethylformimidamide inCH₃CN (20 mL) was added ethylbromoacetate (3.5 g, 21.0 mmol) and themixture was refluxed for 18 h. The reaction mixture was concentrated invacuo and the residue was dissolved in MeCN (20 mL) followed by theaddition of DIPEA (2.7 g, 21.0 mmol) at 0° C. Then, the reaction mixturewas stirred at RT for 3 h, concentrated in vacuo, and the residuefiltered through a silica gel pad using DCM. The filtrate wasconcentrated in vacuo, and the resulting residue was purified by flashcolumn chromatography on silica gel (pet ether/EtOAc, 2:1) to give ethyl6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylate as a pale yellowsolid (80 mg) and ethyl6-chloro-7-methylimidazo[1,2-b]pyridazine-3-carboxylate as a yellowsolid (600 mg).

Ethyl 6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylate: ¹H NMR(500 MHz, CDCl₃): δ 8.31 (s, 1H), 7.10 (s, 1H), 4.48 (q, J=7.0 Hz, 2H),2.71 (s, 3H), 1.45 (t, J=7.0 Hz, 3H). LC-MS m/z: 240.1 [M+H]⁺.

Ethyl 6-chloro-7-methylimidazo[1,2-b]pyridazine-3-carboxylate: ¹H NMR(500 MHz, CDCl₃): δ 8.31 (s, 1H), 7.87 (s, 1H), 4.47 (q, J=7.0 Hz, 2H),2.51 (s, 3H), 1.44 (t, J=7.0 Hz, 3H). LC-MS m/z: 240.1 [M+H]⁺.

Following general procedure B, ethyl6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (80 mg, 0.33mmol) afforded the title compound (60 mg, 80%) as a yellow solid. LC-MSm/z: 212.1 [M+H]⁺.

6-Chloro-7-methylimidazo[1,2-b]pyridazine-3-carboxylic acid

Following general procedure B, ethyl6-chloro-7-methylimidazo[1,2-b]pyridazine-3-carboxylate (160 mg, 0.67mmol) afforded the title compound (130 mg, 93%) as a yellow solid. LC-MSm/z: 212.1 [M+H]⁺.

2,4-Dimethylimidazo[1,5-b]pyridazine-7-carboxylic acid

Following general procedure E, 3-chloro-4,6-dimethylpyridazine (400 mg,2.81 mmol) afforded 4,6-dimethylpyridazine-3-carbonitrile (342 mg, 91%)as a pale yellow solid. LC-MS m/z: 134.3 [M+H]⁺. LCMS: t_(R)=1.40 min.Purity (254 nm): >99%.

Following general procedure F, 4,6-dimethylpyridazine-3-carbonitrile(342 mg, 2.57 mmol) afforded (4,6-dimethylpyridazin-3-yl)methanaminehydrochloride (400 mg) as a dark brown solid which was used directly inthe next step. LC-MS m/z: 138.3 [M+H]⁺. LCMS: t_(R)=0.31 min.

Following general procedure G, (4,6-dimethylpyridazin-3-yl)methanaminehydrochloride (400 mg) afforded ethyl2-(((4,6-dimethylpyridazin-3-yl)methyl)amino)-2-oxoacetate (580 mg, 95%over two steps) as a pale yellow solid. LC-MS m/z: 238.2 [M+H]⁺. LCMS:t_(R)=1.44 min. Purity (254 nm): >99%.

Following general procedure H, ethyl2-(((4,6-dimethylpyridazin-3-yl)methyl)amino)-2-oxoacetate (580 mg, 2.44mmol) afforded ethyl 2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxylate(530 mg, 96%) as a pale white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 7.60(s, 1H), 6.57 (d, J=1.5 Hz, 1H), 4.52 (q, J=7.0 Hz, 2H), 2.60 (s, 3H),2.53 (s, 3H), 1.48 (t, J=7.0 Hz, 3H). LC-MS m/z: 220.2 [M+H]⁺. LCMS:Purity (214 nm): >99%; t_(R)=1.63 min.

Following general procedure B, ethyl2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxylate (410 mg, 1.87 mmol)afforded the title compound (215 mg, 70%) as a pale white solid. ¹H NMR(500 MHz, DMSO-d₆) δ 8.98 (s, 1H), 7.75 (s, 1H), 6.68 (s, 1H), 2.45 (s,3H), 2.43 (s, 3H). LC-MS m/z: 192.0 [M+H]⁺. LCMS: Purity (254 nm): 92%;t_(R)=1.03 min.

5,7-Dimethylthieno[3,2-b]pyridine-3-carboxylic acid

A mixture of dihydrothiophen-3(2H)-one (40 g, 392.1 mmol) and NH₂OH HCl(40 g, 580 mmol) in MeOH (300 mL) was stirred at RT overnight, pouredinto water (200 mL) and basified with solid NaHCO₃ to pH ˜8. The mixturewas extracted with EA (300 mL×4), dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo, and the resultingresidue was purified by silica gel column chromatography (PE/EA=4/1) toafford thiophen-3-amine (15.0 g, 39%) as a black oil. ¹H NMR (500 MHz,CDCl₃): δ 7.15 (dd, J=5.0 Hz, 3.0 Hz, 1H), 6.67 (dd, J=5.0 Hz, 3.0 Hz,1H), 6.19 (dd, J=5.0 Hz, 3.0 Hz, 1H), 3.63 (brs, 2H).

A mixture of thiophen-3-amine (15 g, 150 mmol), pentane-2,4-dione (15 g,151 mmol) and ZnCl₂/Et₂O (1 mol/L, 15 mL, 15.0 mmol) in EtOH (150 mL)was stirred under reflux overnight. Then, the mixture was concentratedand the resulting residue was purified by silica gel columnchromatography (EA/PE=10 to 100%) to afford a mixture of4-(thiophen-3-ylimino)pentan-2-one and 5,7-dimethylthieno[3,2-b]pyridine(16 g) as a black oil. LC-MS m/z: 182.0 [M+H]⁺. t_(R)=1.70 min.

A mixture of 4-(thiophen-3-ylimino)pentan-2-one and5,7-dimethylthieno[3,2-b]pyridine (10 g, crude) in H₃PO₄ (20 mL) wasstirred overnight at 90° C. The reaction was quenched by the addition ofH₂O (200 mL) and the reaction mixture was neutralized with solid NaOHuntil pH >8. The mixture was then extracted with EA (300 mL×3), driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated invacuo, and the resulting residue was purified by silica gel columnchromatography (PE/EA=9/1) to afford 5,7-dimethylthieno[3,2-b]pyridine(5.2 g, 53%) as a red-brown oil. ¹H NMR (500 MHz, CDCl₃): δ 7.69 (d,J=5.5 Hz, 1H), 7.52 (d, J=5.5 Hz, 1H), 6.98 (s, 1H), 2.66 (s, 3H), 2.58(s, 3H). LC-MS m/z: 164.1 [M+H]⁺. t_(R)=1.10 min.

To a mixture of 5,7-dimethylthieno[3,2-b]pyridine (4.2 g, 25.7 mmol),NaHCO₃ (2.16 g, 25.7 mmol), K₂HPO₄ (6.72 g, 38.6 mmol), and MgSO₄ (4.0g, 33.4 mmol) in CHCl₃ (100 mL) under N₂ was added a solution of Br₂(4.93 g, 30.8 mmol) in CHCl₃ (10 ml) dropwise under reflux. After theaddition was complete the mixture was quenched with saturated NaHCO₃,extracted with DCM (150 mL×3) and dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo, and the resultingresidue was purified by silica gel column chromatography (PE/EA=25/1 to4/1) to afford 3-bromo-5,7-dimethylthieno[3,2-b]pyridine (3.2 g, 52%) asa light yellow solid. LC-MS m/z: 241.9 [M+H]⁺. t_(R)=1.76 min.

A mixture of 3-bromo-5,7-dimethylthieno[3,2-b]pyridine (2.06 g, 8.54mmol), Pd(dppf)Cl₂.DCM (697 mg, 0.85 mmol) and Et₃N (2.59 g, 25.62 mmol)in CH₃OH (150 mL) was stirred at 80° C. under CO (10 atm) for 20 h. Themixture was concentrated and the resulting residue was purified bysilica gel column chromatography (PE/EA=9/1 to 4/1) to afford methyl5,7-dimethylthieno[3,2-b]pyridine-3-carboxylate (1.1 g, 58%) as a yellowoil. ¹H NMR (500 MHz, CDCl₃): δ 8.56 (s, 1H), 7.06 (s, 1H), 4.00 (s,3H), 2.76 (s, 3H), 2.58 (s, 3H). LC-MS m/z: 222.1 [M+H]⁺. t_(R)=1.61min.

Following general procedure B, methyl5,7-dimethylthieno[3,2-b]pyridine-3-carboxylate (1.0 g, 4.52 mmol)afforded 5,7-dimethylthieno[3,2-b]pyridine-3-carboxylic acid (500 mg,53%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ 9.14 (s, 1H), 7.61(s, 1H), 2.79 (s, 3H), 2.71 (s, 3H). LC-MS m/z: 207.9 [M+H]⁺. t_(R)=1.17min.

Part III—Compounds Prepared Following General Procedures

The following compounds were prepared based on the general proceduresdescribed in Part I above.

6,8-Dimethyl-N-((1S,4S)-4-(pentyloxy)cyclohexyl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylic acid (30 mg, 0.16mmol) and (1R,4R)-4-(pentyloxy)cyclohexan-1-amine afforded the titlecompound (40 mg, 71%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 8.70(d, J=7.5 Hz, 1H), 8.38 (s, 1H), 6.90 (d, J=0.5 Hz, 1H), 4.09-4.06 (m,1H), 3.46 (t, J=6.5 Hz, 2H), 3.33-3.31 (m, 1H), 2.67 (s, 3H), 2.61 (s,3H), 2.21-2.18 (m, 2H), 2.08-2.05 (m, 2H), 1.62-1.32 (m, 10H), 0.92 (1,J=6.5 Hz, 3H). LC-MS m/z: 359.2 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=9.11 min.

6,8-Dimethyl-N-(4-(oxazol-4-yl)phenyl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylic acid (30 mg, 0.16mmol) and 4-(oxazol-4-yl)aniline afforded the title compound (52 mg,95%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ 10.79 (s, 1H), 8.61(s, 1H), 8.47 (s, 1H), 8.32 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.82 (d,J=9.0 Hz, 1H), 7.30 (s, 1H), 2.69 (s, 3H), 2.60 (s, 3H). LC-MS m/z:334.1 [M+H]⁺. HPLC Purity (214 nm): >92%; t_(R)=7.12 min.

N-(2,3-Dihydro-1H-inden-5-yl)-6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylic acid (30 mg, 0.16mmol) and 2,3-dihydro-1H-inden-5-amine afforded the title compound (44mg, 91%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆): δ 10.65 (s, 1H),8.28 (s, 1H), 7.67 (s, 1H), 7.49 (d, J=10.0 Hz, 1H), 7.29 (s, 1H), 7.23(d, J=10.0 Hz, 1H), 2.89 (t, J=9.0 Hz, 2H), 2.84 (t, J=9.0 Hz, 2H), 2.67(s, 3H), 2.60 (s, 3H), 2.07-2.00 (m, 2H). LC-MS m/z: 307.3 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=8.77 min.

6,8-Dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylic acid (30 mg, 0.16mmol) and 1,2,3,4-tetrahydronaphthalen-1-amine afforded the titlecompound (41 mg, 82%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 9.09(d, J=8.5 Hz, 1H), 8.44 (s, 1H), 7.47 (d, J=7.0 Hz, 1H), 7.21-7.14 (m,3H), 6.87 (d, J=0.5 Hz, 1H), 5.53-5.49 (m, 1H), 2.93-2.83 (m, 2H), 2.67(s, 3H), 2.45 (s, 3H), 2.28-2.23 (m, 1H), 1.98-1.94 (m, 3H). LC-MS m/z:321.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.15 min.

6,8-Dimethyl-N-(1-phenylpropyl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylic acid (30 mg, 0.16mmol) and 1-phenylpropan-1-amine afforded the title compound (34 mg,68%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 9.24 (d, J=8.0 Hz,1H), 8.37 (s, 1H), 7.41-7.34 (m, 4H), 7.26-7.25 (m, 1H), 6.91 (d, J=1.0Hz, 1H), 5.20 (q, J=7.5 Hz, 1H), 2.67 (s, 3H), 2.63 (s, 3H), 2.06-1.94(m, 2H), 1.00 (t, J=7.5 Hz, 3H). LC-MS m/z: 309.2 [M+H]⁺. HPLC Purity(214 nm): >98%; t_(R)=7.97 min.

6,8-Dimethyl-N-(1-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylic acid (40 mg, 0.21mmol) and 1-methyl-1,2,3,4-tetrahydronaphthalen-1-amine afforded thetitle compound (5.4 mg, 8%) as a yellow solid. ¹H NMR (500 MHz, CDCl₃):δ 9.19 (s, 1H), 8.32 (d, J=4.0 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H),7.24-7.17 (m, 2H), 7.13 (d, J=8.0 Hz, 1H), 6.85 (d, J=1.0 Hz, 1H),2.93-2.74 (m, 3H), 2.66 (s, 3H), 2.47 (s, 3H), 2.17-2.13 (m, 1H),1.97-1.92 (m, 2H), 1.90 (s, 3H). LC-MS m/z: 335.2 [M+H]⁺. HPLC Purity(214 nm): >97%; t_(R)=9.26 min.

N-(4-Ethynylphenyl)-6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylic acid (40 mg, 0.21mmol) and 4-ethynylaniline afforded the title compound (6.0 mg, 10%) asa yellow solid. ¹H NMR (500 MHz, CDCl₃): δ 10.87 (s, 1H), 8.50 (s, 1H),7.74 (d, J=8.5 Hz, 2H), 7.53 (d, J=9.0 Hz, 2H), 6.98 (s, 1H), 3.07 (s,1H), 2.72 (s, 3H), 2.71 (s, 3H). LC-MS m/z: 291.1 [M+H]⁺. HPLC Purity(214 nm): >98%; t_(R)=8.45 min.

6-Chloro-N-((1S,4S)-4-(hexyloxy)cyclohexyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (30 mg, 0.14mmol) and (1R,4R)-4-(hexyloxy)cyclohexan-1-amine afforded the titlecompound (13.5 mg, 24%) as a yellow solid. ¹H NMR (500 MHz, CDCl₃): δ8.43 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 7.07 (d, J=1.0 Hz, 1H), 4.08-4.06(m, 1H), 3.46 (t, J=13.5 Hz, 2H), 3.34-3.31 (m, 1H), 2.73 (s, 3H),2.20-2.17 (m, 2H), 2.08-2.05 (m, 2H), 1.33-1.28 (m, 12H), 0.91 (t,J=13.0 Hz, 3H). LC-MS m/z: 393.3 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=11.75 min.

6-Chloro-N-(2,3-dihydro-1H-inden-5-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (21 mg, 0.10mmol) and 2,3-dihydro-1H-inden-5-amine afforded the title compound (20mg, 63%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 10.14 (s, 1H),8.53 (s, 1H), 7.68 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz,1H), 7.12 (s, 1H), 2.97 (t, J=7.5 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.76(s, 1H), 2.12-2.09 (m, 2H). LC-MS m/z: 323.2 [M+H]⁺. HPLC Purity (214nm): >95%; t_(R)=10.90 min.

6-Chloro-7-methyl-N-((1S,4S)-4-(pentyloxy)cyclohexyl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloro-7-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (40 mg, 0.18mmol) and (1R,4R)-4-(pentyloxy)cyclohexan-1-amine afforded the titlecompound (51 mg, 710%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 8.42(s, 1H), 8.12 (d, J=7.5 Hz, 1H), 7.92 (d, J=1.0 Hz, 1H), 4.08-4.07 (m,1H), 3.46 (t, J=13.5 Hz, 2H), 3.33-3.32 (m, 1H), 2.52 (s, 3H), 2.19-2.17(m, 2H), 2.07-2.05 (m, 2H), 1.59-1.33 (m, 10H), 0.91 (t, J=7.0 Hz, 3H).LC-MS m/z: 379.3 [M+H]⁺. HPLC Purity (214 nm): >98%; t_(R)=11.4 min.

6-Chloro-N-(2,3-dihydro-1H-inden-5-yl)-7-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloro-7-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (50 mg, 0.24mmol) and 2,3-dihydro-1H-inden-5-amine afforded the title compound (30mg, 39%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄): δ 10.05 (s, 1H),8.53 (s, 1H), 7.97 (d, J=0.5 Hz, 1H), 7.69 (s, 1H), 7.44 (d, J=8.0 Hz,1H), 7.24 (d, J=8.0 Hz, 1H), 2.96 (t, J=15.0 Hz, 2H), 2.91 (t, J=15.0Hz, 2H), 2.56 (s, 3H), 2.12-2.09 (m, 2H). LC-MS m/z: 327.1 [M+H]⁺. HPLCPurity (254 nm): >99%; t_(R)=10.8 min.

6-Chloro-7-methyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloro-7-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (30 mg, 0.14mmol) and 1,2,3,4-tetrahydronaphthalen-1-amine afforded the titlecompound (32 mg, 67%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 8.50(d, J=9.5 Hz, 2H), 7.91 (d, J=1.0 Hz, 1H), 7.46 (d, J=7.0 Hz, 1H),7.19-7.14 (m, 3H), 5.53-7.51 (m, 1H), 2.92-2.85 (m, 2H), 2.49 (s, 3H),2.25-2.24 (m, 1H), 2.00-1.94 (m, 3H). LC-MS m/z: 341.2 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=10.25 min.

6-Chloro-7-methyl-N-(1-phenylpropyl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloro-7-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (40 mg, 0.18mmol) and -phenylpropan-1-amine afforded the title compound (30 mg, 64%)as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 8.67 (d, J=8.0 Hz, 1H),8.41 (s, 1H), 7.93 (g, J=1.0 Hz, 1H), 7.41-7.25 (m, 5H), 5.20 (q, J=7.5Hz, 1H), 2.52 (s, 3H), 2.04-1.96 (m, 2H), 0.99 (t, J=14.5 Hz, 3H). LC-MSm/z: 329.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=10.22 min.

6-Chloro-N-(2,3-dihydro-1H-inden-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid (38 mg, 0.19 mmol),and 2,3-dihydro-1H-inden-5-amine afforded the title compound (29 mg,49%) as an off-white solid. ¹H NMR (500 MHz, DMSO-d₆): δ 10.21 (s, 1H),8.44-8.42 (m, 2H), 7.65-7.63 (m, 2H), 7.44 (dd, J=8.0, 1.5 Hz, 1H), 7.24(d, J=8.0 Hz, 1H), 2.89 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H),2.07-2.03 (m, 2H). LC-MS m/z: 313.1 [M+H]⁺. HPLC Purity (214 nm): >95%;t_(R)=8.77 min.

6-Chloro-N-(1,2,3,4-tetrahydronaphthalen-1-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid (38 mg, 0.19 mmol)and 1,2,3,4-tetrahydronaphthalen-1-amine afforded the title compound (42mg, 66%) as a light yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.64 (d,J=8.5 Hz, 1H), 8.39 (d, J=10.0 Hz, 1H), 8.36 (s, 1H), 7.57 (d, J=9.0 Hz,1H), 7.36 (d, J=7.0 Hz, 1H), 7.21-7.14 (m, 3H), 5.30-5.26 (m, 1H),2.87-2.76 (m, 2H), 2.12-2.08 (m, 1H), 1.92-1.84 (m, 3H). LC-MS m/z:327.1 [M+H]⁺. HPLC Purity (214 min): >99%; t_(R)=8.16 min.

6-Chloro-N-(4-ethynylphenyl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid (40 mg, 0.20 mmol)and 4-ethynylaniline afforded the compound (13 mg, 22%) as a yellowsolid. ¹H NMR (500 MHz, DMSO-d₆): δ 10.45 (s, 1H), 8.47 (s, 1H), 8.43(d, J=9.5 Hz, 1H), 7.77 (d, J=9.0 Hz, 2H), 7.64 (d, J=9.5 Hz, 1H), 7.52(d, J=9.0 Hz, 2H), 4.15 (s, 1H). LC-MS m/z: 297.1 [M+H]⁺. HPLC Purity(214 nm): 95%; t_(R)=7.82 min.

(S)—N-(1-Cyclopropylethyl)-6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylic acid (30 mg, 0.14mmol) and (S)-1-cyclopropylethanamine afforded the title compound (3.3mg, 8%) as a yellow solid. ¹H NMR (500 MHz, CDCl₃): δ 8.75 (brs, 1H),8.38 (s, 1H), 6.90 (s, 1H), 3.81-3.76 (m, 1H), 2.68 (s, 3H), 2.63 (s,3H), 1.36 (d, J=6.5 Hz, 1H), 1.03-0.99 (m, 1H), 0.58-0.45 (m, 3H),0.35-0.31 (m, 1H). LC-MS m/z: 259.2 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=8.93 min.

N-(2-Cyclopropylpropan-2-yl)-6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylic acid (30 mg, 0.14mmol) and 2-cyclopropylpropan-2-amine afforded the title compound (2.9mg, 7%) as a light yellow solid. ¹H NMR (500 MHz, CDCl₃): δ 8.80 (s,1H), 8.35 (d, J=1.0 Hz, 1H), 6.89 (s, 1H), 2.68 (s, 3H), 2.61 (s, 3H),1.46 (s, 6H), 1.40-1.34 (m, 1H), 0.55-0.50 (m, 4H). LC-MS m/z: 273.2[M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.83 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylic acid (100 mg, 0.46mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride affordedthe title compound (65 mg, 45%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.08 (d, J=9.0 Hz, 1H), 8.26 (s, 1H), 7.28 (s, 1H),4.52-4.43 (m, 1H), 2.60 (s, 3H), 2.59 (s, 3H), 1.35-1.27 (m, 1H),0.71-0.66 (m, 1H), 0.62-0.58 (m, 2H), 0.40-0.38 (m, 1H). LC-MS m/z:313.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.79 min.

N-(2-Cyclopropylpropan-2-yl)-6-(4-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure C, 3,6-dichloro-4-methylpyridazine (10 g, 61mmol) and 4-fluorophenylboronic acid afforded3-chloro-6-(4-fluorophenyl)-4-methylpyridazine (7 g, 51%) as a whitesolid. LC-MS m/z: 223.2 [M+H]⁺.

A mixture of 3-chloro-6-(4-fluorophenyl)-4-methylpyridazine (4.9 g, 22mmol), hydrazine hydrate (5 mL) in i-PrOH (10 mL) was stirred at 120° C.for 2 days in a sealed tube. The mixture was cooled, and concentrated invacuo. The residue was purified by silica gel column chromatography(DCM/MeOH=10:1) to afford6-(4-fluorophenyl)-3-hydrazinyl-4-methylpyridazine (3 g, 62%) as a whitesolid. LC-MS m/z: 219.1 [M+H]⁺.

A mixture of 6-(4-fluorophenyl)-3-hydrazinyl-4-methylpyridazine (3 g,13.7 mmol) and Raney nickel (1.3 g) in MeOH (50 mL) was stirred at RTfor 2 h under H₂, and filtered. The filtrate was concentrated in vacuoto afford crude 6-(4-fluorophenyl)-4-methylpyridazin-3-amine (1.3 g,48%) as a white solid, which was used directly. LC-MS m/z: 204.2 [M+H]⁺.

A solution of 6-(4-fluorophenyl)-4-methylpyridazin-3-amine (300 mg, 1.5mmol) in DMF-DMA (5 mL) was stirred at 100° C. for 4 h, cooled andconcentrated in vacuo to afford crudeN′-(6-(4-fluorophenyl)-4-methylpyridazin-3-yl)-N,N-dimethylformimidamide(380 mg, 100%) as a white solid, which was used. LC-MS m/z: 259.2[M+H]⁺.

A mixture ofN′-(6-(4-fluorophenyl)-4-methylpyridazin-3-yl)-N,N-dimethylformimidamide(380 mg, 1.5 mmol), ethyl bromoacetate (500 mg, 3 mmol) and DIPEA (580mg, 4.5 mmol) in DMF (5 mL) was stirred at 130° C. for 4 h, cooled anddiluted with water (50 mL). The mixture was extracted with EA (50 mL×3).The organic layers were dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo, and the residue was purified byprep-TLC plate to afford ethyl6-(4-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (240mg, 55%) as a yellow solid. LC-MS m/z: 300.2 [M+H]⁺.

Following general procedure B, ethyl6-(4-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (240mg, 0.8 mmol) afforded6-(4-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid(240 mg, 77%) as a yellow solid. LC-MS m/z: 272.1 [M+H]⁺.

Following general procedure A,6-(4-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid(120 mg, 0.44 mmol) and 2-cyclopropylpropan-2-amine afforded the titlecompound (20 mg, 13%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄) δ 8.30(s, 1H), 8.11 (dd, J=8.5 Hz, 5.5 Hz, 2H), 7.79 (d, J=1.0 Hz, 1H), 7.34(t, J=9.0 Hz, 2H), 2.76 (d, J=1.0 Hz, 3H), 1.47 (s, 6H), 1.47-1.41 (m,1H), 0.54-0.52 (m, 4H). LC-MS m/z: 353.2 [M+H]⁺. HPLC: Purity (254 nm):99.75%; t_(R)=10.81 min.

(S)—N-(1-Cyclopropylethyl)-6-(4-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-(4-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid(120 mg, 0.44 mmol) and (S)-1-cyclopropylethanamine afforded the titlecompound (16 mg, 11%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄) δ 8.32(s, 1H), 8.11 (dd, J=8.5 Hz, 5.5 Hz, 2H), 7.84 (s, 1H), 7.38 (t, J=9.0Hz, 2H), 3.71-3.64 (m, 1H), 2.77 (s, 3H), 1.42 (d, J=6.5 Hz, 3H),1.17-1.08 (m, 1H), 0.68-0.60 (m, 1H), 0.60-0.57 (m, 1H), 0.49-0.41 (m,1H), 0.41-0.38 (m, 1H). LC-MS m/z: 339.1 [M+H]⁺. HPLC: Purity (254 nm):99.59%; t_(R)=10.31 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-8-methyl-6-(pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure C, 3,6-dichloro-4-methylpyridazine (5.0 g,30.86 mmol) and pyridin-3-ylboronic acid afforded3-chloro-4-methyl-6-(pyridin-3-yl)pyridazine (1.6 g, 25%), as a whitesolid. LC-MS m/z: 206.0 [M+H]⁺. t_(R)=1.55 min.

A mixture of 3-chloro-4-methyl-6-(pyridin-3-yl)pyridazine (750 mg, 3.65mmol) and N₂H₄.H₂O (85%, 1 mL) in propan-2-ol (15 mL) was stirred at120° C. overnight in a sealed tube, cooled and concentrated in vacuo toafford the crude 3-hydrazinyl-4-methyl-6-(pyridin-3-yl)pyridazine. LC-MSm/z: 202.1 [M+H]⁺. t_(R)=1.26 min.

A mixture of crude 3-hydrazinyl-4-methyl-6-(pyridin-3-yl)pyridazine(previous step) and Raney Ni (100 mg, 1 mL) in MeOH (20 mL) was stirredat RT overnight under H₂, and filtrated. The filtrate was concentratedin vacuo, and the residue was purified by prep-TLC (DCM:MeOH=10:1) toafford 4-methyl-6-(pyridin-3-yl)pyridazin-3-amine (pure: 140 mg; impure:200 mg). LC-MS m/z: 187.1 [M+H]⁺. t_(R)=1.29 min.

A mixture of 4-methyl-6-(pyridin-3-yl)pyridazin-3-amine (140 mg) inDMF-DMA (2 mL) was stirred at 120° C. for 2 hours, cooled andconcentrated in vacuo to afford crudeN,N-dimethyl-N′-(4-methyl-6-(pyridin-3-yl)pyridazin-3-yl)formimidamide.LC-MS m/z: 242.1 [M+H]⁺. t_(R)=1.50 min.

A mixture ofN,N-dimethyl-N′-(4-methyl-6-(pyridin-3-yl)pyridazin-3-yl)formimidamide(crude, previous step), ethyl 2-bromoacetate (125 mg, 1.50 mmol) andDIPEA (290 mg, 2.25 mmol) in DMF (5 mL) was stirred at 120° C. for 2hours, cooled and diluted with water. The mixture was extracted with EA(30 mL×3) and the organic phases were dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo, and the residue waspurified by prep-TLC (EA) to afford ethyl8-methyl-6-(pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxylate (20 mg)as a white solid. LC-MS m/z: 283.1 [M+H]⁺. t_(R)=1.55 min.

Following general procedure B, ethyl8-methyl-6-(pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxylate (20 mg,0.07 mmol) afforded8-methyl-6-(pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxylic acid.LC-MS m/z: 255.1 [M+H]⁺. t_(R)=1.05 min.

Following general procedure A,8-methyl-6-(pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxylic acid and1-cyclopropyl-2,2,2-trifluoroethanamine afforded the title compound as awhite solid (4.4 mg, 17% two steps). ¹H NMR (500 MHz, MeOD-d₄) δ 9.26(d, J=2.0 Hz, 1H), 8.78 (dd, J=4.5 Hz, 1.0 Hz, 1H), 8.52 (dt, J=7.5 Hz,2.0 Hz, 1H), 8.44 (s, 1H), 7.97 (s, 1H), 7.71 (dd, J=8.5 Hz, 5.5 Hz,1H), 4.47-4.40 (m, 1H), 2.83 (s, 3H), 1.35-1.28 (m, 1H), 0.84-0.78 (m,1H), 0.71-0.62 (m, 2H), 0.53-0.47 (m, 1H). LC-MS m/z: 376.0 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=7.16 min.

N-(2-Cyclopropylpropan-2-yl)-6-(3-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure C, 3,6-dichloro-4-methylpyridazine (8.1 g,50.0 mmol), and 3-fluorophenylboronic acid afforded3-chloro-6-(3-fluorophenyl)-4-methylpyridazine (2.0 g, 14%) as a pinksolid. LC-MS m/z: 223.1 [M+H]⁺; t_(R)=1.46 min.

A mixture of 3-chloro-6-(3-fluorophenyl)-4-methylpyridazine (1.0 g, 4.5mmol), and hydrazine hydrate (4 mL) in i-PrOH (40 mL) was stirred at100° C. overnight to afforded6-(3-fluorophenyl)-3-hydrazinyl-4-methylpyridazine which was useddirectly in the next step. LC-MS m/z: 219.2 [M+H]⁺; t_(R)=1.14 min.

To the mixture above was added MeOH (20 mL) and Raney Ni (1.0 g). Theresulting mixture was stirred at RT under H₂ overnight, and filtered.The filtrate was concentrated in vacuo and the residue was purified bysilica gel column chromatography (1% MeOH in EA) to afford6-(3-fluorophenyl)-4-methylpyridazin-3-amine (140 mg, 15%) as a greysolid. LC-MS m/z: 204.2 [M+H]⁺; t_(R)=1.18 min.

A mixture of 6-(3-fluorophenyl)-4-methylpyridazin-3-amine (140 mg,crude) in DMF-DMA (3 mL) was stirred at 110° C. for 2 h, diluted withH₂O (40 mL), and extracted with EA (50 mL×3). The combined organicphases were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to affordN′-(6-(3-fluorophenyl)-4-methylpyridazin-3-yl)-N,N-dimethylformimidamide(3.1 g, crude) as a black oil, which was used in the next step withoutfurther purification. LC-MS m/z: 259.2 [M+H]⁺; t_(R)=1.40 min.

A mixture ofN′-(6-(3-fluorophenyl)-4-methylpyridazin-3-yl)-N,N-dimethylformimidamide(3.1 g, crude), ethyl 2-bromoacetate (228 mg, 1.36 mmol), and DIPEA (263mg, 2.04 mmol) in DMF (8 mL) was stirred at 120° C. for 2 h, cooled,poured into H₂O (20 mL), and extracted with EA (40 mL×3). The combinedorganic phases were dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo and purified by silica gel columnchromatography (PE/EA=4:1) to afford ethyl6-(3-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (100mg, 49%) as a grey solid. LC-MS m/z: 300.1 [M+H]⁺; t_(R)=1.53 min.

Following general procedure B, ethyl6-(3-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (100mg, 0.33 mmol) afforded6-(3-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid(40 mg, 44%) as a grey solid. LC-MS m/z: 272.0 [M+H]⁺; t_(R)=1.25 min.

Following general procedure A,6-(3-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid(40 mg, 0.15 mmol) and 2-cyclopropylpropan-2-amnne afforded the titlecompound (19 mg, 36%) as a light yellow solid. ¹H NMR (500 MHz,DMSO-d₆): β 8.69 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.95-7.91 (m, 2H),7.69-7.64 (m, 1H), 7.44 (td, J=9.0 Hz, 2.5 Hz, 1H), 2.70 (s, 3.H),1.44-1.40 (m, 1H), 1.38 (s, 6H), 0.48-0.43 (m, 4H). LC-MS m/z: 353.2[M+H]⁺. HPLC: Purity (214 nm): >96%; t_(R)=8.90 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-6-(3-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-(3-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid(30 mg, 0.11 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (18 mg, 41%) as a yellowsolid. ¹H NMR (500 MHz, DMSO-d₆): δ 9.10 (d, J=9.5 Hz, 1H), 8.37 (s,1H), 8.05 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.91 (dt, J=8.0 Hz, 2.0 Hz,1H), 7.68 (dd, J=14.0 Hz, 8.0 Hz, 1H), 7.46 (td, J=8.0 Hz, 2.0 Hz, 1H),4.52-4.43 (m, 1H), 2.73 (s, 3H), 1.30-1.23 (m, 1H), 0.74-0.68 (m, 1H),0.66-0.55 (m, 2H), 0.43-0.37 (m, 1H). LC-MS m/z: 393.1 [M+H]⁺. HPLC:Purity (214 nm): 99.81%; t_(R)=8.73 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-6-(3-methoxyphenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure C, 3,6-dichloro-4-methylpyridazine (5 g,30.7 mmol), and 3-methoxyphenylboronic afforded3-chloro-6-(3-methoxyphenyl)-4-methylpyridazine (1.8 g, 26%) as a whitesolid. LC-MS m/z: 235.1 [M+H]⁺; Purity (254 nm): >90%; t_(R)=1.43 min.

A mixture of 3-chloro-6-(3-methoxyphenyl)-4-methylpyridazine (2.6 g,11.11 mmol), and hydrazine hydrate (7 mL) in i-PrOH (70 mL) was stirredat 100° C. overnight. LCMS showed6-(3-methoxyphenyl)-3-hydrazinyl-4-methylpyridazine was successfullygenerated, which was used directly in the next step. LC-MS m/z: 231.2[M+H]⁺; t_(R)=1.12 min.

To the mixture above was added EA (100 mL) and Raney Ni (2.4 g). Theresulting mixture was stirred at RT under H₂ for 3 h, and filtered. Thefiltrate was concentrated in vacuo and purified by silica gel columnchromatography (1% MeOH in EA) to afford6-(3-methoxyphenyl)-4-methylpyridazin-3-amine (500 mg, 20%) as a brownsolid. LC-MS m/z: 216.1 [M+H]⁺; t_(R)=1.16 min.

A mixture of 6-(3-methoxyphenyl)-4-methylpyridazin-3-amine (400 mg, 1.86mmol) in DMF-DMA (3 mL) was stirred at 110° C. for 2 h until that wascompletely converted toN′-(6-(3-methoxyphenyl)-4-methylpyridazin-3-yl)-N,N-dimethylformimidamide.To the reaction mixture was added ethyl 2-bromoacetate (372 mg, 2.23mmol) and DIPEA (480 mg, 3.72 mmol). The mixture was stirred for 2 h atRT and then poured into H₂O (300 mL) and extracted with EA (100 mL×3).The combined organic layers were dried over anhydrous Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo, and the residue waspurified by silica gel column chromatography (pet ether/EA=4:1) toafford ethyl6-(3-methoxyphenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (200mg, 49%) as a brown solid. LC-MS m/z: 312.1 [M+H]⁺; t_(R)=1.51 min.

Following general procedure B, ethyl6-(3-methoxyphenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (240mg, 0.77 mmol) afforded6-(3-methoxyphenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid(80 mg, 30%) as a yellow solid. LC-MS m/z: 284.1 [M+H]⁺; Purity (254nm): >80%; t_(R)=0.93 min.

Following general procedure A,6-(3-methoxyphenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid(20 mg, 0.07 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (4.5 mg, 20%) as a whitesolid. ¹H NMR (500 MHz, DMSO-d₆): δ 9.14 (d, J=10.0 Hz, 1H), 8.36 (s,1H), 8.02 (s, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.60 (t, J=2.5 Hz, 1H), 7.54(t, J=8.0 Hz, 1H), 7.18 (dd, J=8.5 Hz, 2.5 Hz, 1H), 4.52-4.46 (m, 1H),3.87 (s, 3H), 2.72 (s, 3.H), 1.26-1.20 (m, 1H), 0.73-0.67 (m, 1H),0.67-0.55 (m, 2H), 0.42-0.36 (m, 1H). LC-MS m/z: 405.2 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R)=8.70 min.

N-(Dicyclopropylmethyl)-6-(3-methoxyphenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-(3-methoxyphenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid(20 mg, 0.07 mmol) and dicyclopropylmethanamine afforded the titlecompound (4.7 mg, 20%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.79 (d, J=9.0 Hz, 1H), 8.26 (s, 1H), 7.99 (s, 1H), 7.68 (d, J=7.5 Hz,1H), 7.63 (t, J=2.5 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.18 (dd, J=7.5 Hz,2.5 Hz, 1H), 3.88 (s, 3H), 3.40-3.34 (m, 1H), 2.71 (s, 3.H), 1.12-1.05(m, 2H), 0.55-0.50 (m, 2H), 0.45-0.39 (m, 6H). LC-MS m/z: 377.2 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=8.70 min.

N-(2-Cyclopropylpropan-2-yl)-6-(isothiazol-5-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

A mixture of 3,6-dichloro-4-methylpyridazine (10 g, 61.7 mmol) andconcentrated NH₄OH solution (100 ml) was heated at 135° C. in a sealedautoclave for 20 h at 20 bar, cooled to RT, diluted with water (200 mL)and stirred in an ice bath for 2 h. The solid was collected byfiltration, washed with water and dried in vacuo to afford a mixture of6-chloro-5-methylpyridazin-3-amine and6-chloro-4-methylpyridazin-3-amine (7.9 g, 90%) as a yellow solid. LC-MSm/z: 114.1 [M+H]⁺.

The suspension of a mixture of 6-chloro-5-methylpyridazin-3-amine and6-chloro-4-methylpyridazin-3-amine (7.5 g, 55.2 mmol) in DMF-DMA (30 mL)was stirred under reflux for 4 h, and concentrated in vacuo to afford amixture ofN′-(6-chloro-5-methylpyridazin-3-yl)-N,N-dimethylformimidamide andN′-(6-chloro-4-methylpyridazin-3-yl)-N,N-dimethylformimidamide, whichwas used for the next step directly. LC-MS m/z: 199.1 [M+H]⁺.

The mixture ofN′-(6-chloro-5-methylpyridazin-3-yl)-N,N-dimethylformimidamide andN′-(6-chloro-4-methylpyridazin-3-yl)-N,N-dimethylformimidamide (previousstep) and ethylbromoacetate (27.6 g, 165.6 mmol) in MeCN (150 mL) wasrefluxed for 48 h, and concentrated in vacuo. The residue was dissolvedin MeCN (80 mL), and DIPEA (22 g, 165.6 mmol) was added at 0° C. Thereaction mixture was stirred at RT for 3 h, and concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(PE/EA: 1/1) to afford ethyl6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (1.9 g, 14% over2 steps) and ethyl6-chloro-7-methylimidazo[1,2-b]pyridazine-3-carboxylate (3.8 g, 28% over2 steps) as yellow solids.

Ethyl 6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylate: ¹H NMR(500 MHz, CDCl₃): δ 8.31 (s, 1H), 7.10 (s, 1H), 4.48 (q, J=7.0 Hz, 2H),2.71 (s, 3H), 1.45 (t, J=7.0 Hz, 3H). LC-MS m/z: 240.0 [M+H]⁺. Purity(214 nm): 85%; t_(R)=2.21 min.

Ethyl 6-chloro-7-methylimidazo[1,2-b]pyridazine-3-carboxylate: ¹H NMR(500 MHz, CDCl₃): δ 8.31 (s, 1H), 7.87 (s, 1H), 4.47 (q, J=7.0 Hz, 2H),2.51 (s, 3H), 1.44 (t, J=7.0 Hz, 3H). LC-MS m/z: 240.0 [M+H]⁺. Purity(214 nm): 91%; t_(R)=2.17 min.

To a solution of ethyl6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (239 mg, 1 mmol)in dioxane (30 ml) was added Bu₆Sn₂ (1160 mg, 2 mmol),5-bromoisothiazole (326 mg, 2 mmol) and Pd(dppf)Cl₂-DCM (73.1 mg, 0.1mmol). The mixture was purged three times with N₂, then stirred underreflux for 20 h, and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (EA) to afford ethyl6-(isothiazol-5-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (90mg, 31%) as a yellow solid. LC-MS m/z: 289.0 [M+H]⁺. Purity (214 nm):81%; t_(R)=2.29 min.

Following general procedure B, ethyl6-(isothiazol-5-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (98mg, 0.34 mmol) afforded6-(isothiazol-5-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acidlithium salt (80 mg, 90%). LC-MS m/z: 261.1 [M+H]⁺. Purity (254 nm):96%; t_(R)=1.75 min.

Following general procedure A,6-(isothiazol-5-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid(40 mg, 0.15 mmol) and 2-cyclopropylpropan-2-amine afforded the titlecompound (28 mg, 54%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄): δ8.68 (s, 1H), 8.34 (s, 1H), 8.09 (d, J=1.5 Hz, 1H), 7.92 (s, 1H), 2.80(s, 3H), 1.55-1.51 (m, 1H), 1.55 (s, 6H), 0.61-0.56 (m, 4H). LC-MS m/z:342.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.86 min.

6-(Isothiazol-5-yl)-8-methyl-N-(2-methylbut-3-yn-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-(isothiazol-5-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid(40 mg, 0.15 mmol) and 2-methylbut-3-yn-2-amine afforded the titlecompound (20.7 mg, 41%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄): δ8.67 (s, 1H), 8.37 (s, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 2.90 (s, 1H),2.80 (s, 3H), 1.89 (s, 6H). LC-MS m/z: 326.1 [M+H]⁺. HPLC Purity (214nm): >99%; t_(R)=7.04 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-6-(isothiazol-5-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-(isothiazol-5-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid(40 mg, 0.15 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (19 mg, 33%) as a white solid.¹H NMR (500 MHz, MeOD-d₄): δ 8.69 (d, J=1.5 Hz, 1H), 8.44 (s, 1H), 8.11(d, J=1.5 Hz, 1H), 7.98 (s, 1H), 4.44-4.39 (m, 1H), 2.82 (s, 3H),1.40-1.36 (m, 1H), 0.88-0.82 (m, 1H), 0.74-0.64 (m, 2H), 0.56-0.51 (m,1H). LC-MS m/z: 382.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.01min.

(S)-6-(Benzo[d]oxazol-5-yl)-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure B, ethyl6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (1.0 g, 4.18mmol) afforded 6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylicacid (560 mg, 63%) as a white solid. LC-MS m/z: 212.1 [M+H]⁺. t_(R)=1.41min.

Following general procedure A,6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (200 mg,0.95 mmol) and (S)-1-cyclopropylethanamine afforded(S)-6-chloro-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(180 mg, 57%) as a yellow solid. LC-MS m/z: 279.0 [M+H]⁺. Purity (214nm): 92%; t_(R)=1.73 min.

Following general procedure C,(S)-6-chloro-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.36 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (29 mg, 11%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.90 (s, 1H), 8.84 (d, J=7.0 Hz, 1H), 8.57 (d, J=1.0 Hz, 1H),8.26 (s, 1H), 8.20 (dd, J=8.5 Hz, 1.5 Hz, 1H), 8.10 (s, 1H), 8.05 (d,J=8.5 Hz, 1H), 3.66-3.59 (m, 1H), 2.72 (s, 3H), 1.31 (d, J=6.5 Hz, 3H),1.15-1.05 (m, 1H), 0.59-0.51 (m, 2H), 0.43-0.32 (m, 2H). LC-MS m/z:362.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=7.43 min.

6-(Benzo[d]oxazol-5-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (400 mg,1.89 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamine hydrochlorideafforded6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(240 mg, 38%) as a white solid. LC-MS m/z: 333.0 [M+H]⁺. t_(R)=1.82 min.

Following general procedure C,6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(40 mg, 0.12 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (20 mg, 40%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.19 (d, J=9.0 Hz, 1H), 8.90 (s, 1H), 8.53 (s, 1H), 8.36 (s,1H), 8.16 (d, J=8.5 Hz, 1H), 8.13 (s, 1H), 8.04 (d, J=8.5 Hz, 1H),4.52-4.46 (m, 1H), 2.73 (s, 3H), 1.28-1.26 (m, 1H), 0.73-0.60 (m, 3H),0.42-0.37 (m, 1H). LC-MS m/z: 416.0 [M+H]⁺. HPLC: Purity (214 nm): 99%;t_(R)=7.99 min.

6-(Benzo[d]oxazol-4-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure C,6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(75 mg, 0.23 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (1.5 mg, 2%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.70 (d, J=9.5 Hz, 1H), 9.03 (s, 1H), 8.40 (s, 1H), 8.30 (s,1H), 8.19 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.70 (t, J=8.0 Hz,1H), 4.43-4.39 (m, 1H), 2.76 (s, 3H), 1.46-1.41 (m, 1H), 0.79-0.62 (m,2H), 0.59-0.56 (m, 1H), 0.36-0.30 (m, 1H). LC-MS m/z: 416.1 [M+H]⁺.HPLC: Purity (214 nm): 99%; t_(R)=8.44 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-6-(6-methoxypyridin-2-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(80 mg, 0.24 mmol) and 2-methoxy-6-(tributylstannyl)pyridine affordedthe title compound (11 mg, 11%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.09 (d, J=9.2 Hz, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 7.98 (t,J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 4.47-4.39(m, 1H), 4.03 (m, 3H), 2.74 (s, 3H), 1.33-1.28 (m, 1H), 0.72-0.56 (m,3H), 0.42-0.37 (m, 1H). LC-MS m/z: 406.0 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=9.19 min.

6-(3-Fluorophenyl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-(3-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid(150 mg, 0.20 mmol) and 1,1,1-trifluoropropan-2-amine hydrochlorideafforded the title compound (3.5 mg, 7% yield). ¹H NMR (400 MHz,MeOD-d₄) δ 8.40 (s, 1H), 7.90 (s, 1H), 7.88 (d, J=7.2 Hz, 1H), 7.80 (d,J=10.0 Hz, 1H), 7.63 (dd, J=14.0 Hz, 8.0 Hz, 1H), 7.35 (t, J=8.0 Hz,1H), 5.09-5.00 (m, 1H), 2.79 (s, 3H), 1.52 (d, J=7.2 Hz, 3H). LC-MS m/z:367.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=9.80 min.

6-(Benzo[d]oxazol-7-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure C,6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(70 mg, 0.21 mmol) and7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (4.9 mg, 6%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.22 (d, J=8.0 Hz, 1H), 8.92 (s, 1H), 8.43 (s, 1H), 8.15 (s,2H), 8.06 (d, J=8.0 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 4.50-4.42 (m, 1H),2.76 (s, 3H), 1.32-1.26 (m, 1H), 0.73-0.35 (m, 4H). LC-MS m/z: 416.1[M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.09 min.

6-(Benzo[d]oxazol-7-yl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (300 mg,1.42 mmol) and 1,1,1-trifluoropropan-2-amine hydrochloride afforded6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(410 mg, 94%) as a white solid. LC-MS m/z: 307.0 [M+H]⁺. Purity (214nm): 97.8%; t_(R)=1.74 min.

Following general procedure C,6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(70 mg, 0.23 mmol) and7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (19 mg, 22%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 9.09 (d, J=9.6 Hz, 1H), 8.93 (s, 1H), 8.41 (s, 1H), 8.15 (d,J=8.0 Hz, 1H), 8.14 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.66 (t, J=8.0 Hz,1H), 5.11-5.05 (m, 1H), 2.75 (s, 3H), 1.46 (d, J=7.2 Hz, 3H). LC-MS m/z:390.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.28 min.

6-(Benzo[d]oxazol-5-yl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure C,6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.33 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (61 mg, 48%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.08 (d, J=9.0 Hz, 1H), 8.90 (s, 1H), 8.53 (d, J=1.0 Hz,1H), 8.35 (s, 1H), 8.16 (dd, J=8.5 Hz, 1.5 Hz, 1H), 8.12 (s, 1H), 8.03(d, J=8.5 Hz, 1H), 5.05-5.01 (m, 1H), 2.72 (s, 3H), 1.46 (d, J=7.0 Hz,3H). LC-MS m/z: 390.0 [M+H]⁺. HPLC: Purity (214 nm): 91%; t_(R)=7.91min.

6-(2-Cyano-4-fluorophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure C,6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.30 mmol) and 2-cyano-4-fluorophenylboronic acid afforded thetitle compound (40 mg, 32%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆):δ 8.82 (d, J=9.0 Hz, 1H), 8.44 (s, 1H), 8.20 (d, J=7.5 Hz, 1H), 8.08 (t,J=7.5 Hz, 1H), 7.89 (t, J=7.5 Hz, 1H), 7.83 (s, 1H), 4.40-4.30 (m, 1H),2.74 (s, 3H), 1.35-1.25 (m, 1H), 0.70-0.62 (m, 2H), 0.53-0.49 (m, 1H),0.37-0.33 (m, 1H). LC-MS m/z: 418.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.95 min.

6-(2-Cyano-4-fluorophenyl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure C,6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.33 mmol) and 2-cyano-4-fluorophenylboronic acid afforded thetitle compound (7.2 mg, 9%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.69 (d, J=9.5 Hz, 1H), 8.44 (s, 1H), 8.21 (dd, J=9.0 Hz,2.5 Hz, 1H), 8.09 (dd, J=9.0 Hz, 5.5 Hz, 1H), 7.89 (td, J=9.0 Hz, 2.5Hz, 1H), 7.83 (s, 1H), 5.06-4.97 (m, 1H), 2.73 (s, 3H), 1.43 (d, J=7.0Hz, 3H). LC-MS m/z: 392.0 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.58 min.

(S)-6-(2-Cyano-4-fluorophenyl)-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure C,(S)-6-chloro-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(80 mg, 0.29 mmol) and 2-cyano-4-fluorophenylboronic acid afforded thetitle compound (16 mg, 15%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.52 (d, J=8.0 Hz, 1H), 8.34 (s, 1H), 8.22 (dd, J=8.5 Hz, 2.5 Hz, 1H),8.11 (dd, J=8.5 Hz, 5.0 Hz, 1H), 7.89 (td, J=9.0 Hz, 3.0 Hz, 1H), 7.80(s, 1H), 3.60-3.52 (m, 1H), 2.73 (s, 3H), 1.28 (d, J=6.0 Hz, 3H),1.11-1.03 (m, 1H), 0.49-0.19 (m, 4H). LC-MS m/z: 364.1 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R)=8.53 min.

6-(3-Cyanophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure C,6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.30 mmol) and 3-cyanophenylboronic acid afforded the titlecompound (52 mg, 43%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄): δ8.47 (s, 1H), 8.43 (s, 1H), 8.38 (d, J=7.5 Hz, 1H), 7.98 (d, J=7.5 Hz,1H), 7.82 (t, J=7.5 Hz, 1H), 4.48-4.42 (m, 1H), 2.82 (s, 3H), 1.34-1.30(m, 1H), 0.84-0.80 (m, 1H), 0.72-0.62 (m, 2H), 0.55-0.50 (m, 1H). LC-MSm/z: 399.8 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.33 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-6-(3,3-difluoropyrrolidin-1-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

A suspension of6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.30 mmol), 3,3-difluoropyrrolidine hydrochloride (86 mg, 0.60mmol) and DIEA (116 mg, 0.90 mmol) in NMP (3 mL) was stirred at 150° C.for 2 h. The mixture was purified by pre-HPLC (MeCN/NH₄HCO₃) to affordthe title compound (19 mg, 16%) as a pink powder. ¹H NMR (500 MHz,DMSO-d₆): δ 9.22 (d, J=9.0 Hz, 1H), 8.06 (s, 1H), 7.06 (d, J=1.0 Hz,1H), 4.41-4.37 (m, 1H), 4.00-3.90 (m, 2H), 3.80-3.71 (m, 2H), 2.67-2.61(m, 2H), 2.56 (s, 3H), 1.28-1.24 (m, 1H), 0.70-0.62 (m, 1H), 0.62-0.57(m, 2H), 0.38-0.34 (m, 1H). LC-MS m/z: 404.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.32 min.

6-(3-Cyanofuran-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(149 mg, 0.45 mmol) and 2-(tributylstannyl)furan-3-carbonitrile affordedthe title compound (59.6 mg, 34%) as a light yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.59 (d, J=9.2 Hz, 1H), 8.45 (s, 1H), 8.30 (d, J=1.6 Hz,1H), 7.85 (s, 1H), 7.33 (d, J=2.0 Hz, 1H), 4.32-4.21 (m, 1H), 2.73 (s,3H), 1.59-1.51 (m, 1H), 0.75-0.63 (m, 2H), 0.57-0.50 (m, 1H), 0.36-0.30(m, 1H). LC-MS m/z: 389.8 [M+H]⁺. HPLC: Purity (214 nm): 97%; t_(R)=8.31min.

2,4-Dimethyl-N-(4-(oxazol-4-yl)phenyl)imidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxylic acid (30 mg, 0.16mmol) and 4-(oxazol-4-yl)aniline afforded the tile compound (15 mg, 29%)as a yellow solid. ¹H NMR (500 MHz, CDCl₃): δ 10.43 (s, 1H), 7.95 (s,2H), 7.87 (d, J=8.5 Hz, 2H), 7.78 (d, J=8.5 Hz, 2H), 7.66 (s, 1H), 6.58(s, 1H), 2.65 (s, 3H), 2.56 (s, 3H). LC-MS m/z: 334.2 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=8.96 min.

N-(4-Ethynylphenyl)-2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxylic acid (30 mg, 0.16mmol) and 4-ethynylaniline afforded the title compound (30 mg, 66%) as ayellow solid. ¹H NMR (500 MHz, CDCl₃): δ 7.83 (d, J=8.5 Hz, 2H), 7.80(s, 1H), 7.52 (d, J=8.5 Hz, 2H), 6.87 (s, 1H), 3.49 (s, 1H), 2.68 (s,3H), 2.62 (s, 3H). LC-MS m/z: 291.1 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=9.62 min.

N-((1S,4S)-4-Pentyloxycyclohexyl)-2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxylic acid (30 mg, 0.16mmol) and (1R,4R)-4-(pentyloxy)cyclohexan-1-amine afforded the titlecompound (17 mg, 30%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.43(d, J=7.6 Hz, 1H), 7.59 (s, 1H), 6.50 (d, J=0.8 Hz, 1H), 4.12-4.06 (m,1H), 3.45 (t, J=13.6 Hz, 2H), 3.31-3.27 (m, 1H), 2.56 (s, 3H), 2.52 (s,3H), 2.22-2.18 (m, 2H), 2.08-2.04 (m, 2H), 1.61-1.31 (m, 10H), 0.92 (t,J=13.6 Hz, 3H). LC-MS m/z: 359.3 [M+H]⁺. HPLC Purity (214 nm): >98%;t_(R)=10.65 min.

2,4-Dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)imidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxylic acid (40 mg, 0.21mmol) and 1,2,3,4-tetrahydronaphthalen-1-amine afforded the titlecompound (17 mg, 27%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆): δ10.65 (s, 1H), 7.78 (s, 1H), 7.74 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.21(d, J=8.5 Hz, 1H), 6.84 (s, 1H), 2.88 (t, J=7.5 Hz, 2H), 2.84 (t, J=7.5Hz, 2H), 2.54 (s, 3H), 2.53 (s, 3H), 2.03 (m, J=7.5 Hz, 2H). LC-MS m/z:307.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=10.28 min.

2,4-Dimethyl-N-(1-phenylpropyl)imidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxylic acid (40 mg, 0.21mmol), and 1-phenylpropan-1-amine afforded the title compound (6 mg,10%) as a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ 8.95 (d, J=7.5 Hz, 1H),7.62 (s, 1H), 7.43 (d, J=7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 2H), 7.28 (d,J=7.5 Hz, 1H), 6.52 (d, J=1.0 Hz, 1H), 5.28 (q, J=7.5 Hz, 1H), 2.58 (s,3H), 2.54 (s, 3H), 2.09-1.95 (m, 2H), 0.99 (t, J=7.5 Hz, 3H). LC-MS m/z:309.3 [M+H]⁺. HPLC Purity (214 nm): 99%; t_(R)=9.66 min.

N-(2,3-Dihydro-1H-inden-5-yl)-2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxylic acid (40 mg, 0.21mmol) and 2,3-dihydro-1H-inden-5-amine afforded the title compound (17mg, 27%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆): δ 10.65 (s, 1H),7.78 (s, 1H), 7.74 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.21 (d, J=8.5 Hz,1H), 6.84 (s, 1H), 2.88 (t, J=7.5 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.54(s, 3H), 2.53 (s, 3H), 2.03 (m, J=7.5 Hz, 2H). LC-MS m/z: 307.2 [M+H]⁺.HPLC Purity (214 nm): >99%; t_(R)=10.28 min.

(S)—N-(1-Cyclopropylethyl)-2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxylic acid (30 mg, 0.16mmol) and (S)-1-cyclopropylethanamine afforded the title compound (11.4mg, 28%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 8.44 (d, J=6.0 Hz,1H), 7.58 (s, 1H), 6.49 (d, J=0.5 Hz, 1H), 3.81-3.75 (m, 1H), 2.56 (s,3H), 2.52 (s, 3H), 1.35 (d, J=6.5 Hz, 3H), 1.02-0.97 (m, 1H), 0.60-0.41(m, 3H), 0.33-0.29 (m, 1H). LC-MS m/z: 259.0 [M+H]⁺. HPLC Purity (214nm): 96%; t_(R)=8.88 min.

N-(2-Cyclopropylpropan-2-yl)-2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxylic acid (30 mg, 0.16mmol) and 2-cyclopropylpropan-2-amine afforded the title compound (3 mg,7%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 8.38 (brs, 1H), 7.55(s, 1H), 6.47 (s, 1H), 2.55 (s, 3H), 2.51 (s, 3H), 1.45 (s, 6H),1.43-1.38 (m, 1H), 0.50-0.47 (m, 4H). LC-MS m/z: 273.2 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=9.34 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-b]pyridazine-7-carboxylic acid (20 mg, 0.064mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride affordedthe title compound (13 mg, 65%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.26 (d, J=9.5 Hz, 1H), 7.78 (s, 1H), 6.85 (s, 1H),4.31-4.26 (m, 1H), 2.53 (s, 3H), 2.51 (s, 3H), 1.37-1.33 (m, 1H),0.70-0.67 (m, 1H), 0.61-0.56 (m, 2H), 0.36-0.33 (m, 1H). LC-MS m/z:313.1 [M+H]⁺. HPLC Purity (214 nm): 96%; t_(R)=7.47 min.

N-(2-Cyclopropylpropan-2-yl)-2-(4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure C, 3,6-dichloro-4-methylpyridazine (3.0 g,18.4 mmol) and 4-fluorophenylboronic acid afforded3-chloro-6-(4-fluorophenyl)-4-methylpyridazine (1.88 g, 46%) as a paleyellow solid. LC-MS m/z: 223.0 [M+H]⁺. LCMS: Purity (214 nm): 93.1%;t_(R)=1.77 min.

Following general procedure E,3-chloro-6-(4-fluorophenyl)-4-methylpyridazine (1.88 g, 8.44 mmol)afforded 6-(4-fluorophenyl)-4-methylpyridazine-3-carbonitrile (1.7 g,94%) as a pale green solid. LC-MS m/z: 214.1 [M+H]⁺. LCMS: Purity (214nm): 83.8%; t_(R)=1.76 min.

Following general procedure F,6-(4-fluorophenyl)-4-methylpyridazine-3-carbonitrile (1.7 g, 7.98 mmol)afforded (6-(4-fluorophenyl)-4-methylpyridazin-3-yl)methanaminehydrochloride (2.14 g, 93%) as a dark brown solid, which was useddirectly in the next step. LC-MS m/z: 218.1 [M+H]⁺. LCMS: Purity (254nm): 97%; t_(R)=1.76 min.

Following general procedure G,(6-(4-fluorophenyl)-4-methylpyridazin-3-yl)methanamine hydrochloride(2.14 g, 7.3 mmol) afforded ethyl2-((6-(4-fluorophenyl)-4-methylpyridazin-3-yl)methylamino)-2-oxoacetate(1.7 g, 73%) as a pale green solid. LC-MS m/z: 318.1 [M+H]⁺. LCMS:Purity (254 nm): 69.9%; t_(R)=1.29 min.

Following general procedure H, ethyl2-((6-(4-fluorophenyl)-4-methylpyridazin-3-yl)methylamino)-2-oxoacetate(1.65 g, 5.2 mmol) afforded ethyl2-(4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylate (1.35g, 84.3%) as a pale solid. LC-MS m/z: 300.0 [M+H]⁺. LCMS: Purity (214nm): 85.7%; t_(R)=1.94 min.

Following general procedure B, ethyl2-(4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylate (1.35g, 4.51 mmol) afforded2-(4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acid(1.1 g, 90%) as a pale yellow solid. LC-MS m/z: 272.1 [M+H]⁺. LCMS:Purity (214 nm): 95.6%; t_(R)=1.48 min.

Following general procedure A,2-(4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acid(40 mg, 0.14 mmol) and 2-cyclopropylpropan-2-amine afforded the titlecompound (17.4 mg, 34%) as a yellow solid. ¹H NMR (400 MHz, MeOD-d₄): δ8.11 (dd, J=8.8 Hz, 3.2 Hz, 2H), 7.80 (s, 1H), 7.37 (s, 1H), 7.33 (t,J=8.8 Hz, 2H), 2.69 (s, 3H), 1.47 (s, 6H), 1.47-1.45 (m, 1H), 0.53-0.50(m, 4H). LC-MS m/z: 353.1 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=10.53 min.

(S)—N-(1-Cyclopropylethyl)-2-(4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2-(4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acid(40 mg, 0.14 mmol) and (S)-1-cyclopropylethanamine afforded the titlecompound (23.3 mg, 47%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄) δ8.13 (dd, J=8.8 Hz, 3.2 Hz, 2H), 7.80 (s, 1H), 7.40 (s, 11H), 7.34 (t,J=8.8 Hz, 2H), 3.72-3.62 (m, 1H), 2.70 (s, 3H), 1.41 (d, J=6.8 Hz, 3H),1.17-1.08 (m, 1H), 0.68-0.51 (m, 2H), 0.50-0.42 (m, 1H), 0.40-0.36 (m,1H). LC-MS m/z: 339.1 [M+H]⁺. HPLC: Purity (254 nm): 99%; t_(R)=10.16min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-2-(4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2-(4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acid(50 mg, 0.18 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound as a yellow solid (70 mg,99%). ¹H NMR (500 MHz, DMSO-d₆): δ 8.30 (d, J=9.5 Hz, 1H), 8.18 (td,J=5.5 Hz, 4.0 Hz, 2H), 7.87 (s, 1H), 7.56 (d, J=1.0 Hz, 1H), 7.46 (td,J=9.0 Hz, 2.0 Hz, 2H), 4.30-4.22 (m, 1H), 2.64 (d, J=1.0 Hz, 3H),1.40-1.34 (m, 1H), 0.72-0.70 (m, 1H), 0.64-0.61 (m, 1H), 0.58-0.55 (m,1H), 0.38-0.34 (m, 1H). LC-MS m/z: 393.1 [M+H]⁺. HPLC Purity (254 nm):96%; t_(R)=8.77 min.

N-(2-Cyclopropylpropan-2-yl)-2-(3-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure E,chloro-6-(3-fluorophenyl)-4-methylpyridazine (510 mg, 2.29 mmol)afforded 6-(3-fluorophenyl)-4-methylpyridazine-3-carbonitrile (435 mg,89%) as an off-white solid. LC-MS m/z: 214.1 [M+H]⁺. LCMS: Purity (254nm): 96.3%; t_(R)=1.79 min.

Following general procedure F,6-(3-fluorophenyl)-4-methylpyridazine-3-carbonitrile (435 mg, 2.04 mmol)afforded (6-(3-fluorophenyl)-4-methylpyridazin-3-yl)methanaminehydrochloride (500 mg) as a light brown solid, which was used directlyin the next step. LC-MS m/z: 218.1 [M+H]⁺. LCMS: Purity (254 nm): 93.7%;t_(R)=1.40 min.

Following general procedure G,(6-(3-fluorophenyl)-4-methylpyridazin-3-yl)methanamine hydrochloride(500 mg) afforded ethyl2-((6-(3-fluorophenyl)-4-methylpyridazin-3-yl)methylamino)-2-oxoacetate(423 mg, 65% over 2 steps) as a white solid. LC-MS m/z: 318.1 [M+H]⁺.LCMS: Purity (254 nm): 93.6%; t_(R)=1.29 min.

Following general procedure H, ethyl2-((6-(3-fluorophenyl)-4-methylpyridazin-3-yl)methylamino)-2-oxoacetate(420 mg, 1.320 mmol) afforded ethyl2-(3-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylate (300mg, 76%) as a light yellow solid. LC-MS m/z: 300.0 [M+H]⁺. LCMS: Purity(214 nm): 94.1%; t_(R)=1.47 min.

Following general procedure B, ethyl2-(3-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylate (280mg, 0.94 mmol) afforded2-(3-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acidsodium salt (450 mg, >95% crude yield) as an off-white solid. LC-MS m/z:272.1 [M+H]⁺. LCMS: Purity (214 nm): 94.1%; t_(R)=1.62 min.

Following general procedure A,2-(3-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acidsodium salt (220 mg, 0.736 mmol) and 2-cyclopropylpropan-2-amineafforded the title compound as a yellow solid (15 mg, 12%). ¹H NMR (500MHz, MeOD-d₄): δ 7.92 (d, J=8.0 Hz, 1H), 7.87 (dt, J=8.4 Hz, 2.0 Hz,1H), 7.82 (s, 1H), 7.62 (ddd, J=15.0 Hz, 7.5 Hz, 2.0 Hz, 1H), 7.41 (s,1H), 7.36 (td, J=8.0 Hz, 2.0 Hz, 1H), 2.75 (s, 3H), 1.49 (s, 6H),1.49-1.43 (m, 1H), 0.55 (d, J=7.0 Hz, 4H). LC-MS m/z: 353.2 [M+H]⁺. HPLCPurity (254 nm): 98%; t_(R)=8.70 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-2-(3-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2-(3-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acidsodium salt (150 mg, 0.171 mmol) and1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride afforded the titlecompound as a yellow solid (14 mg, 27%). ¹H NMR (500 MHz, MeOD-d₄): δ7.92 (d, J=7.5 Hz, 1H), 7.89 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.63 (ddd,J=15.0 Hz, 7.0 Hz, 2.0 Hz, 1H), 7.49 (s, 1H), 7.37 (td, J=8.5 Hz, 2.5Hz, 2H), 4.48-4.40 (m, 1H), 2.73 (s, 3H), 1.34-1.26 (m, 1H), 0.84-0.78(m, 1H), 0.70-0.61 (m, 2H), 0.56-0.48 (m, 1H). LC-MS m/z: 393.1 [M+H]⁺.HPLC Purity (254 nm): 92%; t_(R)=8.63 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-2-(3-methoxyphenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure C, 3,6-dichloro-4-methylpyridazine (5 g,30.6 mmol), and 3-methoxyphenylboronic acid afforded3-chloro-6-(3-methoxyphenyl)-4-methylpyridazine (1.88 g, 26%) as a whitesolid. LC-MS m/z: 235.1 [M+H]⁺. LCMS: Purity (214 nm): 93.1%; t_(R)=1.93min.

Following general procedure E,3-chloro-6-(3-methoxyphenyl)-4-methylpyridazine (1 g, 4.26 mmol)afforded 6-(3-methoxyphenyl)-4-methylpyridazine-3-carbonitrile (900 mg,94%) as a pale yellow solid. LC-MS m/z: 226.1 [M+H]⁺. LCMS: Purity (214nm): 93.5%; t_(R)=1.88 min.

Following general procedure F,6-(3-methoxyphenyl)-4-methylpyridazine-3-carbonitrile (900 mg, 4 mmol)afforded (6-(3-methoxyphenyl)-4-methylpyridazin-3-yl)methanaminehydrochloride (1.0 g) as a dark brown solid, which was used directly inthe next step. LC-MS m/z: 230.0 [M+H]⁺. LCMS: Purity (214 nm): 93.5%;t_(R)=1.40 min.

Following general procedure G,(6-(3-methoxyphenyl)-4-methylpyridazin-3-yl)methanamine hydrochloride (1g) afforded ethyl2-((6-(3-methoxyphenyl)-4-methylpyridazin-3-yl)methylamino)-2-oxoacetate(1.14 g, 86% over 2 steps) as a pale green solid. LC-MS m/z: 330.1[M+H]⁺. LCMS: Purity (214 nm): 94.6%; t_(R)=1.60 min.

Following general procedure H, ethyl2-((6-(3-methoxyphenyl)-4-methylpyridazin-3-yl)methylamino)-2-oxoacetate(1.14 g, 3.46 mmol afforded ethyl2-(3-methoxyphenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylate (900mg, 84%) as a white solid. LC-MS m/z: 312.1 [M+H]⁺. LCMS: Purity (214nm): 97.5%; t_(R)=1.45 min.

Following general procedure B, ethyl2-(3-methoxyphenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylate (900mg, 2.89 mmol) afforded2-(3-methoxyphenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acid(741 mg, 90%) as a pale solid. LC-MS m/z: 284.2 [M+H]⁺. LCMS: Purity(254 nm): 83.3%; t_(R)=1.63 min.

Following general procedure A,2-(3-methoxyphenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acid(45 mg, 0.16 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (40 mg, 62%) as a pale yellowsolid. ¹H NMR (500 MHz, DMSO-d₆): δ 9.33 (d, J=9.0 Hz, 1H), 7.87 (s,1H), 7.68 (d, J=8.0 Hz, 1H), 7.64 (s, 1H), 7.57 (s, 1H), 7.51 (t, J=8.0Hz, 1H), 7.17 (d, J=6.5 Hz, 1H), 4.34-4.29 (m, 1H), 3.86 (s, 3H), 2.64(s, 3H), 1.36-1.29 (m, 1H), 0.72-0.66 (m, 1H), 0.65-0.51 (m, 2H),0.40-0.30 (m, 1H). LC-MS m/z: 405.1 [M+H]⁺. HPLC Purity (254 nm): >99%;t_(R)=8.57 min.

2-(3-Fluorophenyl)-4-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2-(3-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylate sodiumsalt (150 mg, 0.20 mmol) and 1,1,1-trifluoropropan-2-amine hydrochlorideafforded the title compound (3.5 mg, 7%) as an off white solid. ¹H NMR(500 MHz, MeOD-d₄) δ 7.92 (d, J=7.5 Hz, 1H), 7.88 (d, J=9.5 Hz, 1H),7.87 (s, 1H), 7.63 (dd, J=14.0 Hz, 8.0 Hz, 1H), 7.48 (s, 1H), 7.37 (dd,J=8.5 Hz, 2.5 Hz, 1H), 5.09-5.02 (m, 1H), 2.73 (s, 3H), 1.54 (d, J=7.0Hz, 3H). LC-MS m/z: 367.1 [M+H]⁺. HPLC: Purity (214 nm): 98%; t_(R)=8.44min.

2-(4-Fluorophenyl)-4-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2-(4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acid(30 mg, 0.11 mmol) and 1,1,1-trifluoropropan-2-amine hydrochlorideafforded the title compound (15 mg, 38%) as a pale solid. ¹H NMR (500MHz, DMSO-d₆) δ 9.18 (d, J=8.5 Hz, 1H), 8.18 (dd, J=8.5 Hz, 5.5 Hz, 2H),7.85 (s, 1H), 7.56 (s, 1H), 7.46 (t, J=8.5 Hz, 2H), 4.96-4.91 (m, 1H),2.64 (s, 3H), 1.42 (d, J=6.5 Hz, 3H). LC-MS m/z: 367.1 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R)=8.46 min.

(S)—N-(1-Cyclopropylethyl)-6-(4-fluorophenyl)-8-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxamide

To a solution of 6-(4-fluorophenyl)-3-hydrazinyl-4-methylpyridazine (100mg, 0.458 mmol) in anhydrous dioxane (5 mL) was added Et₃N (70 mg, 0.688mmol). The mixture was stirred for 5 minutes at RT, followed by theaddition of ethyl oxalyl monochloride (680 mg, 0.545 mmol) dropwise,then stirred at 60° C. for 4 h, and concentrated in vacuo to affordethyl2-(2-(6-(4-fluorophenyl)-4-methylpyridazin-3-yl)hydrazinyl)-2-oxoacetate,which was used directly in the next step.

A solution of ethyl2-(2-(6-(4-fluorophenyl)-4-methylpyridazin-3-yl)hydrazinyl)-2-oxoacetate(not weight) in AcOH (5 mL) was heated at 120° C. for 2 h, andconcentrated in vacuo. The residue was dissolved in 10% NaHCO₃ solution(30 mL) and extracted with EA (20 mL×3). The organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas triturated in a mixed solvent of PE/EA (30/1, 3 mL) and filtered tocollect ethyl6-(4-fluorophenyl)-8-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylateas a white solid (89 mg, 64% two steps). LC-MS m/z: 301.1 [M+H]⁺.t_(R)=1.84 min.

To a solution of (S)-1-cyclopropylethanamine (145 mg, 1.7 mmol) in 10 mLof DCM was added Al(Me)₃ (0.85 mL, 1.7 mmol) dropwise at RT under N₂.The reaction mixture was stirred for 30 min, followed by the addition ofa solution of ethyl6-(4-fluorophenyl)-8-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate(100 mg, 0.34 mmol) in DCM (5 mL), and stirred at RT overnight. Themixture was poured into 50 mL of ice-water, basified to pH value to 8,and extracted with EA (50 mL×3). The organic phases were dried overanhydrous Na₂SO₄, filtered, concentrated in vacuo, and purified bypre-TLC to afford the title compound (30 mg, 28%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 8.94 (d, J=8.4 Hz, 1H), 8.19 (dd, J=8.8 Hz, 5.6Hz, 2H), 8.00 (s, 1H), 7.48 (t, J=8.8 Hz, 2H), 3.61-3.52 (m, 1H), 2.74(s, 3H), 1.30 (d, J=6.4 Hz, 3H), 1.15-1.06 (m, 1H), 0.55-0.41 (m, 2H),0.40-0.32 (m, 1H), 0.31-0.25 (m, 1H). LC-MS m/z: 340.1 [M+H]⁺. HPLC:Purity (214 nm): 97%; t_(R)=7.75 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(pyridin-3-yl)isothiazolo[4,5-b]pyridine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-3-yl)isothiazolo[4,5-b]pyridine-3-carboxylic acid(40 mg, 0.185 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamine affordedthe title compound (6 mg, 9%) as a pale yellow solid. ¹H NMR (500 MHz,CDCl₃) δ 10.25 (d, J=9.0 Hz, 1H), 9.11 (d, J=2.5 Hz, 1H), 8.82 (dd,J=5.0 Hz, 1.5 Hz, 1H), 8.33 (dt, J=7.5 Hz, 2.0 Hz, 1H), 8.01 (s, 1H),7.71 (dd, J=8.0 Hz, 5.0 Hz, 1H), 4.54-4.52 (m, 1H), 2.82 (s, 3H),1.34-1.30 (m, 1H), 0.72-0.68 (m, 1H), 0.68-0.60 (m, 2H), 0.50-0.45 (m,1H). LC-MS m/z: 393.1 [M+H]⁺. HPLC: Purity (214 nm): 95%; t_(R)=8.14min.

(S)—N-(1-Cyclopropylethyl)-5-(6-methoxypyridin-2-yl)-7-methylisothiazolo[4,5-b]pyridine-3-carboxamide

Following general procedure D, methyl5-chloro-7-methylisothiazolo[4,5-b]pyridine-3-carboxylate (100 mg, 0.413mmol) and 2-methoxy-6-(tributylstannyl)pyridine afforded5-(6-methoxypyridin-2-yl)-7-methylisothiazolo[4,5-b]pyridine-3-carboxylicacid (60 mg, 48%) as a yellow solid. LC-MS m/z: 302.1 [M+H]⁺. Purity(214 nm): 68%; t_(R)=0.98 min.

Following general procedure A,5-(6-methoxypyridin-2-yl)-7-methylisothiazolo[4,5-b]pyridine-3-carboxylicacid (40 mg, 0.13 mmol) and (S)-1-cyclopropylethanamine afforded thetitle compound (26 mg, 35%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆)δ 9.79 (d, J=8.0 Hz, 1H), 8.43 (s, 1H), 8.21 (d, J=7.0 Hz, 1H), 8.03 (t,J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 4.22 (s, 3H), 3.94-3.88 (m, 1H),2.84 (s, 3H), 1.32 (d, J=6.5 Hz, 3H), 1.14-1.07 (m, 1H), 0.58-0.42 (m,2H), 0.42-0.39 (m, 1H), 0.39-0.31 (m, 1H). LC-MS m/z: 369.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=9.07 min.

N-(2-Cyclopropylpropan-2-yl)-7-methyl-5-(pyridin-3-yl)isothiazolo[4,5-b]pyridine-3-carboxamide

To a solution of 2-cyanoacetamide (10.0 g, 0.119 mol) and sodium nitrite(10.0 g, 0.145 mol) in water (100 g, 5 mol) was added AcOH (13.3 mL,0.234 mol) dropwise over 30 mins maintaining the temperature below 20°C. with the ice bath. The reaction mixture was then stirred overnight,gradually warming to RT. After 12 h the aqueous layer was extracted withEA (100 mL×2). The combined organic layers were dried over Mg₂SO₄, andfiltered. The filtrate was concentrated in vacuo to afford2-amino-N-hydroxy-2-oxoacetimidoyl cyanide (12 g, 89%) as a white solid.¹H NMR (500 MHz, DMSO-d₆) δ 14.45 (s, 1H), 7.90 (s, 1H), 7.83 (s, 1H).LC-MS m/z: 135.9 [M+Na]⁺. t_(R)=0.33 min.

To a suspension of 2-amino-N-hydroxy-2-oxoacetimidoyl cyanide (10 g, 88mmol) in anhydrous CH₂Cl₂ (100 mL) was added pyridine (8.39 g, 0.10mol). The resulting clear yellow solution was cooled in an ice bathunder an atmosphere of N₂ and TsCl (18.5 g, 97 mmol) was added thereto.The reaction mixture was stirred at 0° C. for 30 minutes and then at RTfor 2 h followed by the addition of DCM (200 mL) was added to thisreaction mixture, which was washed with water (50 mL×3) and brine (100mL). The organic phase was dried over anhydrous Na₂SO₄, and filtered.The filtrate was concentrated in vacuo, and the residue wasrecrystallized from DCM/hexane to afford2-amino-2-oxo-N-(tosyloxy)acetimidoyl cyanide (23 g, 91%) as a whitesolid. LC-MS m/z: 267.9 [M+H]⁺. LC-MS: Purity (214 nm): 75%; t_(R)=1.72min.

To a stirred suspension of 2-amino-2-oxo-N-(tosyloxy)acetimidoyl cyanide(10 g, 37.4 mmol) in ethanol (50 mL) was added ethyl 2-mercaptoacetate(5.38 g, 44.9 mmol) at 0° C., followed by the addition of morpholine(4.89 g, 56.1 mmol) over fifteen minutes. The reaction mixture wasstirred for twenty minutes, and diluted with ice water (150 mL). Theprecipitate was collected by filtration and dried in vacuo to affordethyl 4-amino-3-carbamoylisothiazole-5-carboxylate (5 g, 62%) as a whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.13 (s, 1H), 7.77 (s, 1H), 6.84 (s,2H), 4.30 (q, J=7.0 Hz, 2H), 1.30 (t, J=7.5 Hz, 3H). LC-MS m/z: 215.9[M+Na]⁺. LCMS: Purity (214 nm): 96.9%; t_(R)=1.60 min.

A solution of ethyl 4-amino-3-carbamoylisothiazole-5-carboxylate (2 g,9.30 mmol) in concentrated HCl (12 N, 20 mL) was stirred under refluxfor 12 h, and concentrated in vacuo to afford crude4-aminoisothiazole-3-carboxylic acid as a light green solid. LC-MS m/z:145.0 [M+H]⁺. t_(R)=0.60 min.

To a solution of 4-aminoisothiazole-3-carboxylic acid (crude, preparedin the last step) in methanol (10 mL) was added thionyl chloride (3.3 g,27.9 mmol) dropwise at 0° C. The mixture was stirred 70° C. for 2 h, andconcentrated in vacuo. The residue was diluted with EA (100 mL), washedwith saturated NaHCO₃ (100 mL) and brine (50 mL), dried over anhydrousNa₂SO₄, and filtered. The filtrate was concentrated in vacuo to affordmethyl 4-aminoisothiazole-3-carboxylate (1.03 g, 68% two steps) as brownoil. LC-MS m/z: 159.0 [M+H]⁺. LCMS: Purity (214 nm): 97.8%; t_(R)=1.24min.

The solution of methyl 4-aminoisothiazole-3-carboxylate (910 mg, 5.76mmol) and 4-methyleneoxetan-2-one (580 mg, 6.91 mmol) in AcOH (10 mL)was stirred at 100° C. for 1 h until the reaction was complete andconcentrated in vacuo. The residue was purified by silica gel column(PE/EA: 1/1) to afford methyl4-(3-oxobutanamido)isothiazole-3-carboxylate (1.28 g, 92%) as a whitesolid. LC-MS m/z: 242.9 [M+H]⁺. LC-MS Purity (214 nm): >99%; t_(R)=1.44min.

A suspension of methyl 4-(3-oxobutanamido)isothiazole-3-carboxylate (835mg, 3.45 mmol) in PPA (4.8 g, 44.5 mmol) was stirred at 90° C. for 6 h,cooled to RT and diluted with water (50 mL). After stirring at RT for 1h, the reaction mixture was extracted with EA (50 mL×3). The combinedorganic layers were washed with brine (30 mL), dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated in vacuo, and theresidue was purified by silica gel column (MeOH/EA: 1/20) to affordmethyl 5-hydroxy-7-methylisothiazolo[4,5-b]pyridine-3-carboxylate (380mg, 49%) as a pale solid. ¹H NMR (500 MHz, DMSO-d₆) δ 11.50 (s, 1H),6.08 (s, 1H), 3.99 (s, 3H), 2.48 (s, 3H). LC-MS m/z: 225.1 [M+H]⁺. LCMS:Purity (214 nm): 97.5%; t_(R)=0.88 min.

A solution of methyl5-hydroxy-7-methylisothiazolo[4,5-b]pyridine-3-carboxylate (380 mg, 1.69mmol) in POCl₃ (1.25 g, 8.18 mmol) was stirred at 70° C. for 2 h underN₂, cooled, diluted with DCM (60 mL), and poured into ice. The organicphase was separated, washed with saturated NaHCO₃ (30 mL) and brine (20mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel column(PE/EA 4:1) to afford methyl5-chloro-7-methylisothiazolo[4,5-b]pyridine-3-carboxylate (224 mg, 54%)as a white solid. LC-MS m/z: 243.1 [M+H]⁺. LCMS: Purity (214 nm): 97%;t_(R)=1.81 min.

Following general procedure C, methyl5-chloro-7-methylisothiazolo[4,5-b]pyridine-3-carboxylate (60 mg, 0.248mmol) and 3-pyridylboronic acid afforded a mixture of methyl7-methyl-5-(pyridin-3-yl)isothiazolo[4,5-b]pyridine-3-carboxylate (LC-MSm/z: 286.0 [M+H]⁺. LCMS: Purity (214 nm): 6.51%; t_(R)=1.51 min) and7-methyl-5-(pyridin-3-yl)isothiazolo[4,5-b]pyridine-3-carboxylic acid(LC-MS m/z: 272.0 [M+H]⁺. LCMS: Purity (214 nm): 43%; t_(R)=1.10 min).

Following general procedure B, a crude mixture of methyl7-methyl-5-(pyridin-3-yl)isothiazolo[4,5-b]pyridine-3-carboxylate and7-methyl-5-(pyridin-3-yl)isothiazolo[4,5-b]pyridine-3-carboxylic acid(prepared in the last step) afforded7-methyl-5-(pyridin-3-yl)isothiazolo[4,5-b]pyridine-3-carboxylic acid(35 mg, 49%, two steps) as a pale solid. LC-MS m/z: 272.1 [M+H]⁺. LCMS:Purity (214 nm): 95.8%; t_(R)=0.79 min.

Following general procedure A,7-methyl-5-(pyridin-3-yl)isothiazolo[4,5-b]pyridine-3-carboxylic acid(35 mg, 0.13 mmol) and 2-cyclopropylpropan-2-amine afforded the titlecompound (7 mg, 15%) as a pale yellow solid. ¹H NMR (500 MHz, CDCl₃) δ9.93 (s, 1H), 9.09 (d, J=2.0 Hz, 1H), 8.81 (dd, J=8.0 Hz, 2.0 Hz, 1H),8.31 (dt, J=4.5 Hz, 1.0 Hz, 1H), 7.99 (s, 1H), 7.71 (dd, J=8.0 Hz, 4.5Hz, 1H), 2.82 (s, 3H), 1.42 (s, 6H), 1.42-1.38 (m, 1H), 0.54-0.50 (m,4H). LC-MS m/z: 353.0 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.15min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(pyridin-2-yl)isothiazolo[4,5-b]pyridine-3-carboxamide

Following general procedure D, methyl5-chloro-7-methylisothiazolo[4,5-b]pyridine-3-carboxylate (80 mg, 0.33mmol) and 2-(tributylstannyl)pyridine afforded a mixture of methyl7-methyl-5-(pyridin-3-yl)isothiazolo[4,5-b]pyridine-3-carboxylate (LC-MSm/z: 286.0 [M+H]⁺. LCMS: Purity (214 nm): 55%; t_(R)=1.35 min) and7-methyl-5-(pyridin-2-yl)isothiazolo[4,5-b]pyridine-3-carboxylic acid(LC-MS m/z: 272.0 [M+H]⁺. LCMS: Purity (214 nm): 23%; t_(R)=0.89 mi).

Following general procedure B, a crude mixture of methyl7-methyl-5-(pyridin-2-yl)isothiazolo[4,5-b]pyridine-3-carboxylate and7-methyl-5-(pyridin-2-yl)isothiazolo[4,5-b]pyridine-3-carboxylic acid(prepared in the last step) afforded7-methyl-5-(pyridin-2-yl)isothiazolo[4,5-b]pyridine-3-carboxylic acid(50 mg, 56%, over two steps) as a pale solid. LC-MS m/z: 272.1 [M+H]⁺.LCMS: Purity (214 nm): 73%; t_(R)=0.89 min.

Following general procedure A,7-methyl-5-(pyridin-2-yl)isothiazolo[4,5-b]pyridine-3-carboxylic acid(50 mg, 0.185 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamine affordedthe title compound (4.4 mg, 6.1%) as a pale yellow solid. ¹H NMR (500MHz, CDCl₃) δ 10.31 (d, J=9.5 Hz, 1H), 8.97 (d, J=4.5 Hz, 1H), 8.63 (d,J=8.0 Hz, 1H), 8.52 (s, 1H), 8.16 (td, J=7.5 Hz, 1.5 Hz, 1H), 7.66 (dd,J=12.5 Hz, 5.0 Hz, 1H), 4.56-4.51 (m, 1H), 2.85 (s, 3H), 1.36-1.31 (m,1H), 0.72-0.60 (m, 3H), 0.50-0.46 (m, 1H). LC-MS m/z: 393.1 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=9.02 min.

5-(3-Carbamoylphenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylisothiazolo[4,5-b]pyridine-3-carboxamide

A mixture of methyl5-chloro-7-methylisothiazolo[4,5-b]pyridine-3-carboxylate (50 mg, 0.21mmol), (Bu₃Sn)₂O (246 mg, 0.41 mmol) in toluene (2 mL) was stirred at110° C. for 15 h, cooled and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (DCM/MeOH: 10/1) toafford 5-chloro-7-methylisothiazolo[4,5-b]pyridine-3-carboxylic acid asa yellow solid (70 mg, 90%). LC-MS m/z: 229.1 [M+H]⁺. Purity (214 nm):94.60%; t_(R)=0.86 min.

Following general procedure A,5-chloro-7-methylisothiazolo[4,5-b]pyridine-3-carboxylic acid (55 mg,0.22 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamine hydrochlorideafforded5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylisothiazolo[4,5-b]pyridine-3-carboxamide(55 mg, 69%) LC-MS m/z: 359.0 [M+H]⁺. LC-MS Purity (214 nm): 77.34%;t_(R)=1.62 min.

Following general procedure C,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylisothiazolo[4,5-b]pyridine-3-carboxamide(55 mg, 0.157 mmol) and 3-carbamoylphenylboronic acid afforded the titlecompound (3 mg, 4.4%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ10.30 (d, J=9.5 Hz, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 8.11 (d, J=7.5 Hz,1H), 8.07 (d, J=7.5 Hz, 1H), 8.00 (s, 1H), 7.78 (t, J=7.5 Hz, 1H), 7.64(s, 1H), 4.58-4.52 (m, 1H), 2.82 (s, 3H), 1.34-1.30 (m, 1H), 0.72-0.68(m, 1H), 0.68-0.60 (m, 2H), 0.50-0.45 (m, 1H). LC-MS m/z: 435.1 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=7.79 min.

5-(Benzo[d]oxazol-4-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylisothiazolo[4,5-b]pyridine-3-carboxamide

Following general procedure C, methyl5-chloro-7-methylisothiazolo[4,5-b]pyridine-3-carboxylate (300 mg, 1.24mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazoleafforded ethyl5-(benzo[d]oxazol-4-yl)-7-methylisothiazolo[4,5-b]pyridine-3-carboxylate(70 mg, 17%) as a white solid. LC-MS m/z: 326.1 [M+H]⁺. Purity (214nm): >96%; t_(R)=1.68 min.

A solution of ethyl5-(benzo[d]oxazol-4-yl)-7-methylisothiazolo[4,5-b]pyridine-3-carboxylate(60 mg, 0.184 mmol) and (Bu₃Sn)₂O (219.4 mg, 0.368 mmol) in 3 mL oftoluene was stirred at 120° C. for 24 h, and concentrated in vacuo. Theresidue was stirred in EA (5 mL) and aqueous NaHCO₃ (10 mL) for 10minutes. The aqueous phase was separated, washed with EA (5 mL),acidified with 2N HCl to pH=5, and extracted with EA (10 mL×3). Theorganic phases were washed with brine (5 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to afford5-(benzo[d]oxazol-4-yl)-7-methylisothiazolo[4,5-b]pyridine-3-carboxylicacid as a brown solid (20 mg, 35%). LC-MS m/z: 312.0 [M+H]⁺. Purity (254nm): >43%; t_(R)=1.27 min.

Following general procedure A,5-(benzo[d]oxazol-4-yl)-7-methylisothiazolo[4,5-b]pyridine-3-carboxylicacid (15 mg, 0.048 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (6.6 mg, 24%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (d, J=9.2 Hz, 1H), 8.98 (s,1H), 8.14 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.73(t, J=8.0 Hz, 1H), 4.56-4.50 (m, 1H), 2.83 (s, 3H), 1.34-1.28 (m, 1H),0.72-0.60 (m, 3H), 0.49-0.46 (m, 1H). LC-MS m/z: 433.1 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R)=9.29 min.

N-(2-Cyclopropylpropan-2-yl)-5,7-dimethylthieno[3,2-b]pyridine-3-carboxamide

Following general procedure A,5,7-dimethylthieno[3,2-b]pyridine-3-carboxylic acid (70 mg, 0.34 mmol)and 2-cyclopropylpropan-2-amine afforded the title compound as a yellowsolid (33 mg, 74%). ¹H NMR (500 MHz, CDCl₃): δ 10.05 (s, 1H), 8.50 (s,1H), 6.95 (s, 1H), 2.60 (s, 3H), 2.50 (s, 3H), 1.40 (s, 6H), 1.33-1.30(m, 1H), 0.47-0.44 (m, 4H). LC-MS m/z: 289.1 [M+H]⁺. HPLC Purity (214nm): >99%; t_(R)=11.59 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5,7-dimethylthieno[3,2-b]pyridine-3-carboxamide

Following general procedure A,5,7-dimethylthieno[3,2-b]pyridine-3-carboxylic acid (70 mg, 0.34 mmol)and 1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride afforded thetitle compound (23 mg, 210%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 10.54 (d, J=9.5 Hz, 1H), 8.88 (s, 1H), 7.33 (s, 1H), 7.04(d, J=7.5 Hz, 1H), 4.60-4.56 (m, 1H), 2.65 (s, 3H), 2.59 (s, 3H),1.30-1.25 (m, 1H), 0.69-0.58 (m, 2H), 0.52-0.48 (m, 1H), 0.47-0.41 (m,1H). LC-MS m/z: 329.1 [M+H]⁺. HPLC Purity (214 nm): 98%; t_(R)=11.37min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(pyridin-3-yl)thieno[3,2-b]pyridine-3-carboxamide

A mixture of methyl 4-oxotetrahydrothiophene-3-carboxylate (2.3 g, 14.37mmol) and NH₂OH HCl (1.2 g, 17.25 mmol) in MeOH (40 mL) was stirredunder reflux for 1 h, quenched with saturated NaHCO₃ (200 mL) andextracted with EA (100 mL×3). The combined organic phases were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to affordmethyl 4-aminothiophene-3-carboxylate (2.1 g, 93%) as a light yellowoil. LC-MS m/z: 158.0 [M+H]⁺. t_(R)=1.44 min.

A mixture of methyl 4-aminothiophene-3-carboxylate (157 mg, 1.0 mmol)and 4-methyleneoxetan-2-one (84 mg, 1.0 mmol) in HOAc (2 mL) was stirredat 110° C. for 30 min, and concentrated in vacuo. The residue waspurified by silica gel column chromatography to afford methyl4-(3-oxobutanamido)thiophene-3-carboxylate (80 mg, 33%) as a yellowsolid. ¹H NMR (500 MHz, CDCl₃) δ 10.77 (bs, 1H), 8.07 (s, 2H), 3.95 (s,3H), 3.63 (s, 2H), 2.35 (s, 3H). LC-MS m/z: 242.1 [M+H]⁺. t_(R)=1.53min.

A mixture of methyl 4-(3-oxobutanamido)thiophene-3-carboxylate (390 mg,1.6 mmol) in H₃PO₄ (6 mL) was stirred at 90° C. overnight, quenched withsaturated Na₂CO₃ (200 mL), and extracted with EA (160 mL×3). Thecombined organic phases were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford methyl5-hydroxy-7-methylthieno[3,2-b]pyridine-3-carboxylate (300 mg, 84%) as agrey solid. ¹H NMR (500 MHz, DMSO-d₆) δ 10.40 (s, 1H), 8.70 (s, 1H),6.34 (s, 1H), 3.90 (s, 3H), 2.37 (d, J=1.0 Hz, 3H). LC-MS m/z: 224.1[M+H]⁺. t_(R)=1.41 min.

A mixture of methyl5-hydroxy-7-methylthieno[3,2-b]pyridine-3-carboxylate (600 mg, 2.7 mmol)in POCl₃ (10 mL) was stirred at 110° C. for 2 h, poured into crushedice, and extracted with EA (80 mL×3). The combined organic phases werewashed with saturated NaHCO₃ (200 mL) and brine (200 mL), dried overanhydrous Na₂SO₄, and filtered. The filtrate was concentrated in vacuoto afford methyl 5-chloro-7-methylthieno[3,2-b]pyridine-3-carboxylate(510 mg, 78%) as a grey solid. LC-MS m/z: 242.1 [M+H]⁺. t_(R)=1.71 min.

Following general procedure C, methyl5-chloro-7-methylthieno[3,2-b]pyridine-3-carboxylate (438 mg, 1.81 mmol)and pyridin-3-ylboronic acid afforded crude methyl7-methyl-5-(pyridin-3-yl)thieno[3,2-b]pyridine-3-carboxylate (600 mg) asa light yellow solid. LC-MS m/z: 285.1 [M+H]⁺. t_(R)=1.35 min.

Following general procedure B, crude methyl7-methyl-5-(pyridin-3-yl)thieno[3,2-b]pyridine-3-carboxylate (572 mg)afforded 7-methyl-5-(pyridin-3-yl)thieno[3,2-b]pyridine-3-carboxylicacid (180 mg, 35% yield over two steps) as a grey green solid. ¹H NMR(500 MHz, DMSO-d₆) δ 12.45 (bs, 1H), 9.36 (s, 1H), 9.00 (s, 1H), 8.69(s, 1H), 8.52 (d, J=8.0 Hz, 1H), 8.08 (s, 1H), 7.59 (t, J=6.0 Hz, 1H),2.69 (s, 3H). LC-MS m/z: 271.1 [M+H]⁺. t_(R)=0.89 min.

Following general procedure A,7-methyl-5-(pyridin-3-yl)thieno[3,2-b]pyridine-3-carboxylic acid (27 mg,0.10 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamine afforded thetitle compound (20 mg, 34%) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ10.52 (d, J=9.0 Hz, 1H), 9.27 (d, J=1.5 Hz, 1H), 8.80 (s, 1H), 8.75 (dd,J=4.5 Hz, 1.5 Hz, 1H), 8.35 (dt, J=8.0 Hz, 2.0 Hz, 1H), 7.68 (s, 1H),7.50 (dd, J=8.0 Hz, 5.0 Hz, 1H), 4.52-4.50 (m, 1H), 2.76 (s, 3H),1.29-1.24 (m, 1H), 0.76-0.74 (m, 1H), 0.60-0.52 (m, 3H). LC-MS m/z:392.0 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.64 min.

(S)—N-(1-Cyclopropylethyl)-7-methyl-5-(pyridin-3-yl)thieno[3,2-b]pyridine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-3-yl)thieno[3,2-b]pyridine-3-carboxylic acid (54 mg,0.20 mmol) and (S)-1-cyclohexylethanamine afforded the title compound(16 mg, 31%) as an off-white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 9.91 (d,J=7.5 Hz, 1H), 9.38 (d, J=2.0 Hz, 1H), 8.86 (s, 1H), 8.71 (dd, J=4.5 Hz,1.5 Hz, 1H), 8.51 (dt, J=8.0 Hz, 2.0 Hz, 1H), 8.10 (s, 1H), 7.63 (dd,J=8.0 Hz, 5.0 Hz, 1H), 3.63-3.61 (m, 1H), 2.71 (s, 3H), 1.32 (d, J=6.5Hz, 3H), 1.10-1.08 (m, 1H), 0.56-0.49 (m, 2H), 0.39-0.33 (m, 2H). LC-MSm/z: 338.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.06 min.

5-(3-Carbamoylphenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylthieno[3,2-b]pyridine-3-carboxamide

Following general procedure C, methyl5-chloro-7-methylthieno[3,2-b]pyridine-3-carboxylate (626 mg, 2.6 mmol)and 3-carbamoylphenylboronic acid afforded methyl5-(3-carbamoylphenyl)-7-methylthieno[3,2-b]pyridine-3-carboxylate (625mg, 76%) as a grey solid. LC-MS m/z: 327.1 [M+H]⁺. t_(R)=1.29 min.

Following general procedure B, methyl5-(3-carbamoylphenyl)-7-methylthieno[3,2-b]pyridine-3-carboxylate (100mg, 0.3 mmol) afforded5-(3-carbamoylphenyl)-7-methylthieno[3,2-b]pyridine-3-carboxylic acid(75 mg, 80%) as an off-white solid. LC-MS m/z: 313.1 [M+H]⁺. t_(R)=0.93min.

Following general procedure A,5-(3-carbamoylphenyl)-7-methylthieno[3,2-b]pyridine-3-carboxylic acid(48 mg, 0.15 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (21 mg, 38%) as a white solid.¹H NMR (500 MHz, DMSO-d₆) δ 10.57 (d, J=9.0 Hz, 1H), 9.01 (s, 1H), 8.65(s, 1H), 8.27 (d, J=7.5 Hz, 1H), 8.14 (s, 1H), 8.13 (d, J=7.0 Hz, 1H),8.00 (d, J=8.0 Hz, 1H), 7.67 (t, J=7.5 Hz, 1H), 7.55 (s, 1H), 4.42-4.38(m, 1H), 2.74 (s, 3H), 1.51-1.44 (m, 1H), 0.72-0.69 (m, 1H), 0.68-0.60(m, 2H), 0.40-0.36 (m, 1H). LC-MS m/z: 434.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=7.96 min.

Example 2—Preparation of Additional Compounds

Additional exemplary compounds were prepared based on general proceduresdescribed in Part I below. Exemplary procedures for preparing specificcompounds according to the general procedures are described in Part IIbelow.

Part I—General Procedures

General Procedure A: Preparation of Amide Compound by Coupling of aCarboxylic Acid Compound with an Amine Compound

To a stirred solution of carboxylic acid compound (1.0 equivalent), HATU(1.5 equivalents), and DIPEA (3.75 equivalents) in DCM or DMF (˜4 mL/0.2mmol) was added the amine (1.25-2.0 equivalents). The reaction mixturewas stirred at RT for 4-16 h, and then washed with saturated aqueousNaHCO₃ solution (5 mL/0.2 mmol), aqueous citric acid solution (5 mL/0.2mmol) and brine (5 mL/0.2 mmol). The combined extracts were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude materialwas purified by silica gel column chromatography or preparatory HPLC togive the amide compound.

General Procedure B: Conversion of Carboxylic Ester Compound toCarboxylic Acid Compound

To a solution of carboxylic ester (1.0 equivalent) in EtOH (5.0 mL/1.0mmol) and water (0-3.0 mL/1.0 mmol) was added NaOH (2.0-5.0 equivalents)and the mixture was heated at 80° C. for 2 h and then concentrated. Tothe concentrate, 6N HCl solution was added to adjust the pH to 5-6 andthen the mixture was stirred for 10 minutes and subsequently filtered.The resulting solid was collected and dried to give the carboxylic acidcompound.

Alternatively, to a solution of carboxylic ester (1.0 equivalent) in THF(5.0 mL/1.0 mmol) was added LiOH (1M solution, 3 equivalents) and themixture was stirred for 60° C. for 1-2 h and then the pH was adjusted to˜7 with 1 N HCl. The resulting solution was lyophilized to afford thecrude carboxylic acid.

General Procedure C: Preparation of Amide Compound from a CarboxylicAcid Compound and an Amine Compound Using Oxalyl Chloride

To a solution of carboxylic acid (1.0 equivalent) in DCM (3 mL/0.5 mmol)was added DMF (1 drop) and oxalyl chloride (2.0 equivalents). Thesolution was stirred at RT for 30 min and concentrated in vacuo. Theresidue was dissolved in DCM (1 mL/0.5 mmol) followed by the addition ofthe amine (5.0 equivalents) and triethylamine (2.0 equivalents). Thereaction mixture was stirred at RT for 2 hours and diluted with DCM (10mL/0.5 mmol). The organic solution was washed with H₂O (10 mL/0.5 mmol)and brine (10 mL/0.5 mmol), dried over anhydrous Na₂SO₄, and filtered.The filtrate was concentrated in vacuo, and the residue was purified bypreparatory HPLC or silica gel chromatography to give the amide.

General Procedure D: Preparation of Coupled Aryl and Heteroaryl GroupsUsing Suzuki-Catalyzed Coupling Conditions Between an Organoboronic Acidor Ester and an Aryl Halide or Heteroaryl Halide

A suspension of heteroaryl chloride (1 equivalent), organoboronic acidor organoboronic ester (1.2 equivalents), K₃PO₄ (3.0 equivalents), andPd(dppf)Cl₂.DCM (5 mol %) or Pd₂(dba)₃ (10 mol %) in DME or 1,4-dioxane(40 mL/mmol) was stirred at 70-100° C. for 2-6 hours under N₂. Then, thereaction mixture was concentrated in vacuo and the resulting residue waspurified by silica gel column chromatography to afford the coupled ringsystem.

General Procedure E: Preparation of Coupled Aryl and Heteroaryl GroupsUsing Buchwald Catalyzed Coupling Conditions Between Organohalides inthe Presence of a Tin Reagent

A solution of organobromide (1.0 equivalent), organochloride (1.0equivalent), hexabutylditin (1.0 equivalent), and Pd(dppf)Cl₂.DCM (10mol %) or Pd(t-Bu₃P)₂ in anhydrous 1,4-dioxane (10 mL/mmol) or DMA (10mL/mmol) was stirred at 100° C. under N₂ overnight, then cooled and thereaction quenched with water (20 mL/mmol). The resulting mixture wasextracted with EtOAc (20 mL/mmol×3), the organic phases were separatedand dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo, and the resulting residue was purified by silicagel column chromatography or preparative-TLC to afford the coupled ringsystem.

General Procedure F: Preparation of Coupled Aryl and Heteroaryl GroupsUsing Buchwald Catalyzed Coupling Conditions Between an Organohalide andOrganotin Reagent

A solution of organochloride (1.0 equivalent) and organotin reagent (1.0equivalent) in 1,4-dioxane (20 mL/mmol) was stirred and purged with N₂three times at RT. Then Pd(dppf)Cl₂-DCM (10 mol %) or Pd(PPh₃)₂Cl₂ wasquickly added under a N₂ atmosphere to the reaction mixture, followed byadditional purging with N₂ (×3) and then the mixture was stirred at 120°C. overnight. Next, the reaction was cooled to RT and then quenched withwater (20 mL/mmol). The resulting mixture was extracted with EA (20mL/mmol×3), and the organic phases were dried over anhydrous Na₂SO₄ andfiltered and concentrated in vacuo. The resulting residue was purifiedby silica gel column chromatography or preparative-TLC to afford thecoupled ring system.

General Procedure G: Preparation of Coupled Imidazolidinyl Groups UsingBuchwald Catalyzed Coupling Conditions Between an Organohalide andImidazolidinyl Reagent

A solution of organochloride (1.0 equivalent), imidazolidinyl reagent(1.0-2.0 equivalents), Pd₂(dba)₃ (10 mol %), x-antphos (20 mol %) andCs₂CO₃ (2.1 equivalents) in dioxane (0.3 mmol/5 mL) was stirred at 110°C. for 2 to 16 h under a N₂ atmosphere. The reaction mixture was cooledto RT, quenched with saturated NH₄Cl (20 mL), and extracted with EA (30mL×3). The combined organic layers were washed with brine (30 mL), driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated invacuo, and the residue was purified by silica gel column chromatographyto afford the coupled ring system.

Part II—Compounds Prepared Following General Procedures

The following compounds were prepared based on the general proceduresdescribed in Part I above.

6-(3-Methoxyphenyl)-8-methyl-N-(1,1,1-trifluorobut-3-yn-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-(3-methoxyphenyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid(25 mg, 0.09 mmol) and 1,1,1-trifluorobut-3-yn-2-amine afforded thetitle compound (4.2 mg, 12%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 9.50 (d, J=9.6 Hz, 1H), 8.41 (s, 1H), 8.06 (s, 1H), 7.67 (d, J=7.6 Hz,1H), 7.62 (s, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.18 (dd, J=8.8 Hz, 2.8 Hz,1H), 6.11-6.06 (m, 1H), 3.90 (d, J=2.4 Hz, 1H), 3.88 (s, 3H), 2.72 (s,3H). LC-MS m/z: 389.1 [M+H]⁺. HPLC: Purity (214 nm): 98%; t_(R)=8.51min.

(R)-6-(Benzo[d]oxazol-5-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (300 mg,1.42 mmol) and (R)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochlorideafforded(R)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(310 mg, 66%) as a yellow solid. LC-MS m/z: 333.1 [M+H]⁺. Purity (214nm): 86%; t_(R)=1.80 min.

Following general procedure D,(R)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(90 mg, 0.27 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (44.6 mg, 40%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.18 (d, J=9.0 Hz, 1H), 8.90 (s, 1H), 8.52 (d, J=1.5 Hz, 1H),8.36 (s, 1H), 8.15 (dd, J=9.0 Hz, 2.0 Hz, 1H), 8.11 (d, J=1.0 Hz, 1H),8.02 (d, J=8.5 Hz, 1H), 4.52-4.44 (m, 1H), 2.73 (s, 3H), 1.31-1.20 (m,1H), 0.74-0.65 (m, 1H), 0.66-0.60 (m, 2H), 0.44-0.42 (m, 1H). LC-MS m/z:416.0 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.01 min.

(S)-6-(Benzo[d]oxazol-5-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (300 mg,1.42 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochlorideafforded(S)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(300 mg, 65%) as a yellow solid. LC-MS m/z: 333.1 [M+H]⁺. Purity (214nm): 86%; t_(R)=1.80 min.

Following general procedure D,(S)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(50 mg, 0.150 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (37 mg, 59%) as a yellow solid. ¹H NMR (500 MHz,MeOD-d₄) δ 8.63 (s, 1H), 8.47 (d, J=1.5 Hz, 1H), 8.41 (s, 1H), 8.16 (dd,J=8.5 Hz, 2.0 Hz, 1H), 7.98 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 4.47-4.43(m, 1H), 2.82 (s, 3H), 1.34-1.31 (m, 1H), 0.82-0.79 (m, 1H), 0.70-0.62(m, 2H), 0.53-0.49 (m, 1H). LC-MS m/z: 416.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.03 min.

(R)-6-(Benzo[d]oxazol-5-yl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (250 mg,1.18 mmol) and (R)-1,1,1-trifluoropropan-2-amine hydrochloride afforded(R)-6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(230 mg, 72%) as a yellow solid. LC-MS m/z: 307.0 [M+H]⁺. LCMS:t_(R)=1.71 min.

Following general procedure D,(R)-6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.33 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (80 mg, 63%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.08 (d, J=8.8 Hz, 1H), 8.90 (s, 1H), 8.52 (s, 1H), 8.35 (s,1H), 8.15 (d, J=8.4 Hz, 1H), 8.11 (s, 1H), 8.04 (d, J=8.4 Hz, 1H),5.04-5.02 (m, 1H), 2.72 (s, 3H), 1.48 (d, J=6.8 Hz, 3H). LC-MS m/z:390.1 [M+H]⁺. HPLC: Purity (254 nm): 99%; t_(R)=7.59 min.

(S)-6-(Benzo[d]oxazol-5-yl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (220 mg,1.05 mmol) and (S)-1,1,1-trifluoropropan-2-amine hydrochloride afforded(S)-6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(160 mg, 50%) as a white solid. LC-MS m/z: 307.0 [M+H]⁺, t_(R)=1.75 min.

Following general procedure D,(S)-6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(123 mg, 0.404 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (90 mg, 57%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.07 (d, J=9.5 Hz, 1H), 8.90 (s, 1H), 8.52 (s, 1H), 8.35 (s,1H), 8.16 (dd, J=8.5 Hz, 1.0 Hz, 1H), 8.12 (s, 1H), 8.03 (d, J=8.5 Hz,1H), 5.04-5.00 (m, 1H), 2.72 (s, 3H), 1.46 (d, J=7.0 Hz, 3H). LC-MS m/z:390.1 [M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=7.59 min.

(R)-6-(2-Cyano-4-fluorophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(R)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(90 mg, 0.27 mmol) and 2-cyano-4-fluorophenylboronic acid afforded thetitle compound (19 mg, 17%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄)δ 8.46 (s, 1H), 8.04 (dd, J=8.8 Hz, 4.2 Hz, 1H), 7.89 (dd, J=8.0 Hz, 2.4Hz, 1H), 7.75 (d, J=1.2 Hz, 1H), 7.72 (td, J=8.4 Hz, 2.4 Hz, 1H),4.31-4.27 (m, 1H), 2.82 (s, 3H), 1.39-1.34 (m, 1H), 0.77-0.75 (m, 1H),0.61-0.59 (m, 2H), 0.45-0.43 (m, 1H). LC-MS m/z: 418.1 [M+H]⁺. HPLC:Purity (254 nm): >99%; t_(R)=8.39 min.

(S)-6-(2-Cyano-4-fluorophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(S)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(80 mg, 0.24 mmol) and 2-cyano-4-fluorophenylboronic acid afforded thetitle compound (8.2 mg, 8%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.81 (d, J=9.0 Hz, 1H), 8.44 (s, 1H), 8.19 (dd, J=9.0 Hz, 2.0 Hz, 1H),8.07 (dd, J=9.0 Hz, 5.0 Hz, 1H), 7.89 (td, J=8.5 Hz, 3.0 Hz, 1H), 7.83(d, J=1.0 Hz, 1H), 4.37-4.33 (m, 1H), 2.74 (d, J=1.0 Hz, 3H), 1.30-1.25(m, 1H), 0.70-0.61 (m, 2H), 0.53-0.48 (m, 1H), 0.38-0.33 (m, 1H). LC-MSm/z: 418.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.39 min.

(R)-6-(2-Cyano-4-fluorophenyl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(R)-6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.32 mmol) and 2-cyano-4-fluorophenylboronic acid afforded thetitle compound (14.4 mg, 11%) as a white solid. H NMR (500 MHz, MeOD-d₄)δ 8.46 (s, 1H), 8.05 (dd, J=8.8 Hz, 4.8 Hz, 1H), 7.90 (dd, J=8.4 Hz, 2.8Hz, 1H), 7.75 (d, J=0.8 Hz, 1H), 7.72 (td, J=8.8 Hz, 3.2 Hz, 1H),5.04-5.00 (m, 1H), 2.81 (d, J=0.8 Hz, 3H), 1.52 (d, J=6.8 Hz, 3H). LC-MSm/z: 392.1 [M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=7.99 min.

(S)-6-(2-Cyano-4-fluorophenyl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(S)-6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(76 mg, 0.25 mmol) and 2-cyano-4-fluorophenylboronic acid afforded thetitle compound (3.8 mg, 4%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.69 (d, J=9.5 Hz, 1H), 8.44 (s, 1H), 8.22 (dd, J=8.5 Hz, 3.0 Hz, 1H),8.09 (dd, J=8.5 Hz, 5.0 Hz, 1H), 7.90 (id, J=8.5 Hz, 3.0 Hz, 1H), 7.83(d, J=1.0 Hz, 1H), 5.04-4.99 (m, 1H), 2.74 (d, J=1.0 Hz, 3H), 1.43 (d,J=7.0 Hz, 3H). LC-MS m/z: 392.1 [M+H]⁺. Purity (214 nm): >99%;t_(R)=1.78 min.

(R)-6-(2-Cyano-4-fluorophenyl)-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (180 mg,0.85 mmol) and (R)-1-cyclopropylethanamine afforded(R)-6-chloro-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(200 mg, 85%) as a yellow solid. LC-MS m/z: 279.1 [M+H]⁺. Purity (214nm): 94%; t_(R)=1.26 min.

Following general procedure D,(R)-6-chloro-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.33 mmol) and 2-cyano-4-fluorophenylboronic acid afforded thetitle compound (28.2 mg, 22%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.52 (d, J=8.0 Hz, 1H), 8.34 (s, 1H), 8.22 (dd, J=9.0 Hz, 3.0Hz, 11H), 8.11 (dd, J=9.0 Hz, 5.5 Hz, 1H), 7.89 (td, J=9.0 Hz, 3.0 Hz,1H), 7.80 (s, 1H), 3.60-3.52 (m, 1H), 2.73 (s, 3H), 1.28 (d, J=6.5 Hz,3H), 1.11-1.03 (m, 1H), 0.49-0.41 (m, 1H), 0.40-0.30 (m, 2H), 0.29-0.22(m, 1H). LC-MS m/z: 364.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=7.93 min.

(R)-6-(5-Cyanofuran-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

To a solution of 5-bromofuran-2-carbonitrile (1 g, 10.8 mmol) in 40 mLof anhydrous THF was added n-BuLi (5.6 mL, 14 mmol) at −78° C., followed30 minutes later by the addition of SnBu₃Cl (2.90 mL, 10.8 mmol). Afterstirring at RT overnight, the reaction mixture was quenched withsaturated NH₄Cl (15 mL), and extracted with EA (50 mL×3). The organicphases were washed with H₂O (50 mL) and brine (50 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo, and the residue was purified by preparative HPLC (MeCN/NH₄HCO₃)to afford 5-(tributylstannyl)furan-2-carbonitrile (1 g, 24%) as a yellowoil. LC-MS m/z: 383.1 [M+H]⁺. t_(R)=2.87 min.

Following general procedure F,(R)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.15 mmol) and 5-(tributylstannyl)furan-2-carbonitrile affordedthe title compound (5 mg, 6%) as a yellow solid. ¹H NMR (500 MHz,MeOD-d₄) δ 8.43 (s, 1H), 7.90 (s, 1H), 7.59 (d, J=3.5 Hz, 1H), 7.51 (d,J=3.5 Hz, 1H), 4.56-4.52 (m, 1H), 2.79 (s, 3H), 1.37-1.35 (m, 1H),0.81-0.79 (m, 1H), 0.73-0.71 (m, 1H), 0.62-0.60 (m, 2H). LC-MS m/z:390.1 [M+H]⁺. HPLC: Purity (214 nm): 97%; t_(R)=8.31 min.

(S)-6-(5-Cyanofuran-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure F,(S)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(150 mg, 0.45 mmol) and 5-(tributylstannyl)furan-2-carbonitrile affordedthe title compound (18 mg, 10%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.08 (d, J=9.6 Hz, 1H), 8.40 (s, 1H), 8.00 (s, 1H), 7.89 (d,J=4.0 Hz, 1H), 7.66 (d, J=3.6 Hz, 1H), 4.62-4.55 (m, 1H), 2.70 (s, 3H),1.32-1.23 (m, 1H), 0.70-0.62 (m, 1H), 0.60-0.55 (m, 1H), 0.53-0.47 (m,1H). LC-MS m/z: 390.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.30min.

(R)-6-(3-Cyanothiophen-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

To a solution of 2-bromothiophene-3-carbonitrile (2 g, 10.64 mmol) inanhydrous THF (20 mL) was added n-BuLi (8.5 mL, 21.28 mmol, 2.5Msolution in hexane) at −78° C. under N₂. The mixture was stirred at −78°C. for 1 hour, followed by the addition of Bu₃SnCl (750 mg, 2.0 mmol) at−78° C., and stirred at −78° C. for another hour and then warmed to RT.After concentration, the residue was purified by silica gel columnchromatography (PE/EA: 10/1) to afford2-(tributylstannyl)thiophene-3-carbonitrile (4.2 g, 57%) as colorlessoil. H NMR (500 MHz, CDCl₃) δ 7.54 (d, J=5.0 Hz, 1H), 7.33 (d, J=5.0 Hz,1H), 1.62-1.39 (m, 6H), 1.35-1.13 (m, 12H), 0.92-0.70 (m, 9H).

Following general procedure F,(R)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.3 mmol) and 2-(tributylstannyl)thiophene-3-carbonitrileafforded the title compound (44 mg, 36%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.79 (d, J=9.0 Hz, 1H), 8.43 (s, 1H), 8.11 (d, J=5.5 Hz,1H), 7.94 (s, 1H), 7.74 (d, J=5.5 Hz, 1H), 4.38-4.32 (m, 1H), 2.74 (s,3H), 1.39-1.36 (m, 1H), 0.74-0.65 (m, 2H), 0.59-0.55 (m, 1H), 0.40-0.35(m, 1H). LC-MS m/z: 406.0 [M+H]⁺. HPLC: Purity (254 nm): >99%.t_(R)=8.45 min.

(S)-6-(3-Cyanothiophen-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure F,(S)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.3 mmol) and 2-(tributylstannyl)thiophene-3-carbonitrileafforded the title compound (12 mg, 9%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.79 (d, J=9.0 Hz, 1H), 8.43 (s, 1H), 8.11 (d, J=5.5 Hz,1H), 7.94 (s, 1H), 7.74 (d, J=5.5 Hz, 1H), 4.38-4.32 (m, 1H), 2.74 (s,3H), 1.39-1.36 (m, 1H), 0.74-0.65 (m, 2H), 0.59-0.55 (m, 1H), 0.40-0.35(m, 1H). LC-MS m/z: 406.0 [M+H]⁺. HPLC: Purity (254 nm): >99%.t_(R)=8.45 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-6-(3-isopropyl-2-oxoimidazolidin-1-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure G,6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(60 mg, 0.180 mmol) and 1-isopropylimidazolidin-2-one afforded the titlecompound (50 mg, 49%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄) δ8.49 (d, J=1.0 Hz, 1H), 8.23 (s, 1H), 4.31-4.23 (m, 2H), 4.11-4.03 (m,2H), 3.65 (t, J=8.0 Hz, 2H), 2.68 (s, 3H), 1.33-1.30 (m, 1H), 1.27 (d,J=7.0 Hz, 6H), 0.83-0.78 (m, 1H), 0.70-0.63 (m, 2H), 0.50-0.48 (m, 1H).LC-MS m/z: 425.2 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.31 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-6-(isoxazol-3-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure F, ethyl6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (400 mg, 1.6mmol) and tributyl(vinyl)stannane afforded ethyl8-methyl-6-vinylimidazo[1,2-b]pyridazine-3-carboxylate (350 mg, 91%) asa pale white solid. LC-MS m/z: 232.1 [M+H]⁺. LCMS: Purity (214 nm):89.2%; t_(R)=1.13 min.

To a solution of ethyl8-methyl-6-vinylimidazo[1,2-b]pyridazine-3-carboxylate (350 mg, 1.5mmol) and OsO4 (5 mg, 0.019 mmol) in THF/H₂O (10 mL/3 mL) was addedNaIO₄ (1.28 g, 6 mmol). The resulting mixture was stirred at RT for 12h, and diluted with water (50 mL). The mixture was extracted with EA (20mL×3), and the EA layers were washed with brine (15 mL), dried overanhydrous Na₂SO₄, and filtered. The filtrate was concentrated in vacuoto afford ethyl 6-formyl-8-methylimidazo[1,2-b]pyridazine-3-carboxylate(370 mg, crude) as an oil, which was used directly in the next step.LC-MS m/z: 234.1 [M+H]⁺. LCMS: Purity (254 nm): 60.2%; t_(R)=1.09 min.

To a solution of ethyl6-formyl-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (370 mg) inmethanol (5 mL) were added hydroxylammonium chloride (354 mg, 4.76 mmol)and Et₃N (566 mg, 6.3 mmol). The mixture was stirred at RT for 2 h, andconcentrated in vacuo. The resulting residue was purified by silica gelcolumn chromatography (PE/EA: 1/2) to afford ethyl6-((hydroxyimino)methyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylate(240 mg, 64% over two steps) as a yellow solid. LC-MS m/z: 249.1 [M+H]⁺.LCMS: Purity: 90.1%; t_(R)=1.30 min.

To a solution ethyl6-((hydroxyimino)methyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylate(190 mg, 0.76 mmol) and ethynyltrimethylsilane (90.2 mg, 0.92 mmol) inMeCN (10 mL) was added CrO₂ (332 mg, 4.0 mmol). The reaction mixture wasstirred at 80° C. for 2 hours, and filtered through Celite. The filtratewas concentrated in vacuo, and the residue was purified by silica gelcolumn chromatography (PE/EA: 5/1) to afford ethyl8-methyl-6-(5-(trimethylsilyl)isoxazol-3-yl)imidazo[1,2-b]pyridazine-3-carboxylate(180 mg, 68%) as a yellow solid. LC-MS m/z: 345.1 [M+H]⁺. LCMS: Purity:74.2%; t_(R)=1.59 min.

Following general procedure B, ethyl8-methyl-6-(5-(trimethylsilyl)isoxazol-3-yl)imidazo[1,2-b]pyridazine-3-carboxylate(180 mg, 0.52 mmol) afforded6-(isoxazol-3-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (45mg, 35%) as a pale white solid. LC-MS m/z: 267.1 [M+Na]⁺. LCMS: Purity(254 nm): 79.9%; t_(R)=0.93 min.

Following general procedure A,6-(isoxazol-3-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylic acid (45mg, 0.18 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamine hydrochlorideafforded the title compound (25 mg, 37%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 9.25 (d, J=2.0 Hz, 1H), 8.96 (d, J=9.0 Hz, 1H), 8.41 (s,1H), 7.97 (d, J=1.5 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 4.45-4.40 (m, 1H),2.73 (s, 3H), 1.34-1.32 (m, 1H), 0.70-0.57 (m, 3H), 0.40-0.39 (m, 1H).LC-MS m/z: 366.1 [M+H]⁺. HPLC: Purity (254 nm): 95%; t_(R)=8.01 min.

6-(6-Chloropyridin-2-yl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(90 mg, 0.29 mmol) and2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineafforded the title compound (2.1 mg, 2%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 9.00 (d, J=9.5 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J=7.0 Hz,1H), 8.18 (t, J=8.0 Hz, 1H), 8.13 (d, J=1.0 Hz, 1H), 7.75 (d, J=8.0 Hz,1H), 5.08-4.98 (m, 1H), 2.75 (s, 3H), 1.48 (d, J=7.5 Hz, 3H). LC-MS m/z:384.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.71 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-8-methyl-6-(3-methylisothiazol-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide

To a solution of 5-bromo-3-methylisothiazole (178 mg, 1.0 mmol) inanhydrous THF (10 mL) was added n-BuLi (2.5 mol/L, 0.48 mL) at −78° C.The mixture was stirred for 1 h followed by the dropwise addition ofBu₃SnCl (326 mg, 1.0 mmol) in anhydrous THF (0.5 mL). The mixture wasstirred for 2 h at −78° C., quenched with saturated NH₄Cl (10 mL), andextracted with EA (10 mL×3). The organic phases were dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo,and the residue was purified by preparative TLC (PE:EA=20:1) to afford3-methyl-5-(tributylstannyl)isothiazole (190 mg, 49%) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ 7.00 (s, 1H), 2.55 (s, 3H), 1.59-1.51 (m, 6H),1.38-1.28 (m, 6H), 1.13-1.113 (m, 6H), 0.99-0.88 (m, 9H).

Following general procedure F,(R)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.301 mmol) and 3-methyl-5-(tributylstannyl)isothiazoleafforded the title compound (6 mg, 5%) as a white solid. ¹H NMR (500MHz, MeOD-d₄) δ 8.42 (s, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.91 (s, 1H),4.44-4.40 (m, 1H), 2.81 (d, J=0.5 Hz, 3H), 2.60 (s, 3H), 1.39-1.35 (m,1H), 0.88-0.82 (m, 1H), 0.72-0.63 (m 2H), 0.56-0.51 (m, 1H). LC-MS m/z:396.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.49 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-8-methyl-6-(3-methylisothiazol-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure F,(S)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.301 mmol) and 3-methyl-5-(tributylstannyl)isothiazoleafforded the title compound (31 mg, 26%) as a white solid. ¹H NMR (500MHz, MeOD-d₄) δ 8.42 (s, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.91 (s, 1H),4.44-4.40 (m, 1H), 2.81 (d, J=0.5 Hz, 3H), 2.60 (s, 3H), 1.39-1.35 (m,1H), 0.88-0.82 (m, 1H), 0.72-0.63 (m 2H), 0.56-0.51 (m, 1H). LC-MS m/z:396.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.49 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-6-(2-fluoropyridin-3-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(60 mg, 0.180 mmol) and 2-fluoropyridin-3-ylboronic acid afforded thetitle compound (15 mg, 16%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄)δ 8.50 (td, J=9.5 Hz, 1.5 Hz, 1H), 8.45 (s, 1H), 8.45-8.44 (m, 1H), 7.85(s, 1H), 7.60 (tt, J=6.5 Hz, 1.0 Hz, 1H), 4.42-4.38 (m, 1H), 2.82 (s,3H), 1.30-1.26 (m, 1H), 0.84-0.76 (m, 1H), 0.68-0.61 (m, 2H), 0.48-0.45(m, 1H). LC-MS m/z: 394.0 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.01 min.

(R)-6-(5-Chloropyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D, ethyl6-chloro-8-methylimidazo[1,2-b]pyridazine-3-carboxylate (500 mg, 2.08mmol) and 5-chloropyridin-3-ylboronic acid afforded ethyl6-(5-chloropyridin-3-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylate(100 mg, 15%) as a white solid. LC-MS m/z: 317.1 [M+H]⁺. t_(R)=1.72 min.

Following general procedure B, ethyl6-(5-chloropyridin-3-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylate(100 mg, 0.31 mmol) afforded6-(5-chloropyridin-3-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylicacid (90 mg, 100%) as an off-white solid. LC-MS m/z: 289.0 [M+H]⁺.t_(R)=1.19 min.

Following general procedure A,6-(5-chloropyridin-3-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylicacid (90 mg, 0.311 mmol) and (R)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (21.8 mg, 17%) as a whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ 9.24 (d, J=2.0 Hz, 1H), 9.02 (d,J=9.5 Hz, 1H), 8.85 (d, J=2.5 Hz, 1H), 8.58 (t, J=2.0 Hz, 1H), 8.39 (s,1H), 8.14 (d, J=1.0 Hz, 1H), 4.48-4.42 (m, 1H), 2.72 (s, 3H), 1.30-1.22(m, 1H), 0.74-0.56 (m, 3H), 0.44-0.37 (m, 1H). LC-MS m/z: 410.1 [M+H]⁺.HPLC Purity (214 nm): 99.49%; t_(R)=8.35 min.

(S)-6-(5-Chloropyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure A,6-(5-chloropyridin-3-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxylicacid (70 mg, 0.24 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (31.6 mg, 32%) as a whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ 9.24 (s, 1H), 9.02 (d, J=9.5 Hz, 1H),8.85 (d, J=2.5 Hz, 1H), 8.58 (s, 1H), 8.39 (s, 1H), 8.14 (s, 1H),4.48-4.42 (m, 1H), 2.72 (s, 3H), 1.30-1.22 (m, 1H), 0.74-0.56 (m, 3H),0.44-0.37 (m, 1H). LC-MS m/z: 410.1 [M+H]⁺. HPLC Purity (254 nm): 96%;t_(R)=8.35 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-6-(5-fluoropyridin-3-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(60 mg, 0.180 mmol) and 5-fluoropyridin-3-ylboronic acid afforded thetitle compound (15 mg, 16%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄)δ 9.14 (s, 1H), 8.72 (d, J=3.0 Hz, 1H), 8.44 (s, 1H), 8.34 (dt, J=9.5Hz, 2.0 Hz, 1H), 7.99 (d, J=1.0 Hz, 1H), 4.46-4.40 (m, 1H), 2.83 (s,3H), 1.34-1.30 (m, 1H), 0.83-0.80 (m, 1H), 0.69-0.63 (m, 2H), 0.54-0.49(m, 1H). LC-MS m/z: 394.0 [M+H]⁺. HPLC: Purity (214 nm): 98.72%;t_(R)=7.91 min.

8-Methyl-6-(2-methylbenzo[d]oxazol-5-yl)-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(90 mg, 0.29 mmol) and2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazoleafforded the title compound (2.1 mg, 2%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 9.07 (d, J=9.5 Hz, 1H), 8.34 (s, 1H), 8.33 (d, J=4.0 Hz,1H), 8.05 (s, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H),5.05-5.00 (m, 1H), 2.71 (s, 3H), 2.67 (s, 3H), 1.47 (d, J=7.0 Hz, 3H).LC-MS m/z: 404.1 [M+H]⁺. HPLC: Purity (214 nm): 99%; t_(R)=7.93 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-6-(3,3-difluoropiperidin-1-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

To a solution of(R)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(80 mg, 0.24 mmol) in DMF (2 mL) were added 3,3-difluoropiperidinehydrochloride (76 mg, 0.48 mmol), DIPEA (155 mg, 1.2 mmol) and KI (4 mg,0.024 mmol). The resulting orange mixture was stirred at 150° C. for 4 hunder microwave condition. The reaction mixture was purified bypreparative HPLC (MeCN/NH₄HCO₃) and preparative TLC (PE/EA=1/2) toafford the title compound (15.6 mg, 14%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 9.06 (d, J=9.6 Hz, 1H), 8.06 (s, 1H), 7.46 (s, 1H),4.40-4.35 (m, 1H), 3.95 (t, J=12.4 Hz, 2H), 3.65 (t, J=5.2 Hz, 2H), 2.54(s, 3H), 2.20-2.10 (m, 2H), 1.85-1.78 (m, 2H), 1.20-1.15 (m, 1H),0.72-0.55 (m, 3H), 0.38-0.32 (m, 1H). LC-MS m/z: 418.1 [M+H]⁺. HPLCPurity (214 nm): 99%; t_(R)=8.25 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-6-(3,3-difluoropiperidin-1-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

To a solution of(S)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(65 mg, 0.195 mmol) in DMF (2 mL) were added 3,3-difluoropiperidinehydrochloride (62 mg, 0.39 mmol), DIPEA (129 mg, 0.975 mmol) and KI (3mg, 0.0195 mmol). The resulting orange mixture was stirred at 150° C.for 4 h under microwave condition. The reaction mixture was purified bypreparative HPLC (MeCN/NH₄HCO₃) to afford the title compound (14 mg,17%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 9.05 (d, J=9.5 Hz,1H), 8.06 (s, 1H), 7.45 (d, J=0.5 Hz, 1H), 4.40-4.35 (m, 1H), 3.95 (td,J=12.0 Hz, 3.0 Hz, 2H), 3.65 (t, J=5.0 Hz, 2H), 2.54 (s, 3H), 2.20-2.10(m, 2H), 1.85-1.78 (m, 2H), 1.20-1.15 (m, 1H), 0.72-0.55 (m, 3H),0.38-0.32 (m, 1H). LC-MS m/z: 418.1 [M+H]⁺. HPLC Purity (214 nm): 98%;t_(R)=8.29 min.

6-(2-Cyanophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.301 mmol) and 2-cyanophenyl boronic acid afforded the titlecompound (30 mg, 25%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄) δ8.48 (s, 1H), 8.04 (d, J=7.5 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.94 (t,J=6.5 Hz, 1H), 7.79 (t, J=6.5 Hz, 1H), 7.78 (s, 1H), 4.34-4.30 (m, 1H),2.83 (s, 3H), 1.39-1.36 (m, 1H), 0.78-0.74 (m, 1H), 0.65-0.58 (m, 2H),0.48-0.44 (m, 1H). LC-MS m/z: 400.0 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.21 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-6-(5-fluorofuran-2-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure F,6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.30 mmol) and tributyl(5-fluorofuran-2-yl)stannane affordedthe title compound (9.4 mg, 8%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.14 (d, J=9.5 Hz, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.50 (t,J=3.5 Hz, 1H), 6.19 (dd, J=6.0 Hz, 4.0 Hz, 1H), 4.61-4.56 (m, 1H), 2.66(s, 3H), 1.31-1.20 (m, 1H), 0.70-0.67 (m, 1H), 0.65-0.55 (m, 2H),0.52-0.48 (m, 1H). LC-MS m/z: 383.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.74 min.

(R)-6-(3-Cyano-5-methylfuran-2-yl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure F,(R)-6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(32 mg, 0.10 mmol) and 5-methyl-2-(tributylstannyl)furan-3-carbonitrileafforded the title compound (20 mg, 53%) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.45 (d, J=8.5 Hz, 1H), 8.44 (s, 1H), 7.80 (s, 1H), 6.95(s, 1H), 5.08-5.04 (m, 1H), 2.71 (s, 3H), 2.47 (s, 3H), 1.50 (d, J=7.0Hz, 3H). LC-MS m/z: 378.1 [M+H]⁺. HPLC: Purity (214 nm): 90.8%;t_(R)=8.27 min.

(S)-6-(3-Cyano-5-methylfuran-2-yl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure F,(S)-6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(32 mg, 0.10 mmol) and 5-methyl-2-(tributylstannyl)furan-3-carbonitrileafforded the title compound (19 mg, 50%) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.45 (d, J=8.5 Hz, 1H), 8.44 (s, 1H), 7.80 (s, 1H), 6.95(s, 1H), 5.08-5.04 (m, 1H), 2.71 (s, 3H), 2.47 (s, 3H), 1.50 (d, J=7.0Hz, 3H). LC-MS m/z: 378.1 [M+H]⁺. HPLC: Purity (214 nm): 90.8%;t_(R)=8.27 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-8-methyl-6-(1-methyl-1H-benzo[d]imidazol-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(R)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.3 mmol) and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazoleafforded the title compound (17.5 mg, 14%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 9.31 (d, J=9.0 Hz, 1H), 8.43 (s, 1H), 8.33 (s, 2H), 8.14(s, 1H), 8.01 (dd, J=8.5 Hz, 1.0 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H),4.56-4.46 (m, 1H), 3.92 (s, 3H), 2.72 (s, 3H), 1.30-1.21 (m, 1H),0.77-0.59 (m, 3H), 0.44-0.40 (m, 1H). LC-MS m/z: 429.1 [M+H]⁺. HPLCPurity (214 nm): 99.54%; t_(R)=7.29 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-8-methyl-6-(1-methyl-1H-benzo[d]imidazol-5-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(S)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(80 mg, 0.22 mmol) and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazoleafforded the title compound (40 mg, 39%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 9.31 (d, J=9.0 Hz, 1H), 8.43 (s, 1H), 8.33 (s, 2H), 8.14(s, 1H), 8.01 (dd, J=8.5 Hz, 1.0 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H),4.56-4.46 (m, 1H), 3.92 (s, 3H), 2.72 (s, 3H), 1.30-1.21 (m, 1H),0.77-0.59 (m, 3H), 0.44-0.40 (m, 1H). LC-MS m/z: 429.1 [M+H]⁺. HPLCPurity (214 nm): 93%; t_(R)=7.30 min.

(R)-6-(5-Methylpyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(R)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(80 mg, 0.24 mmol), and 5-methylpyridin-3-ylboronic acid afforded thetitle compound (30 mg, 32%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 9.092 (d, J=9.0 Hz, 1H), 9.088 (s, 1H), 8.63 (s, 1H), 8.38 (s, 1H),8.27 (s, 1H), 8.08 (s, 1H), 4.53-4.48 (m, 1H), 2.72 (s, 3H), 2.42 (s,3H), 1.28-1.24 (m, 1H), 0.73-0.68 (m, 1H), 0.65-0.55 (m, 2H), 0.42-0.37(m, 1H). LC-MS m/z: 390.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=7.76 min.

(S)-6-(5-Methylpyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(S)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(80 mg, 0.24 mmol) and 5-methylpyridin-3-ylboronic acid afforded thetitle compound (21.3 mg, 23%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.092 (d, J=9.0 Hz, 1H), 9.088 (s, 1H), 8.63 (s, 1H), 8.38(s, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 4.53-4.48 (m, 1H), 2.72 (s, 3H),2.42 (s, 3H), 1.28-1.24 (m, 1H), 0.73-0.68 (m, 1H), 0.65-0.55 (m, 2H),0.42-0.37 (m, 1H). LC-MS m/z: 390.1 [M+H]⁺. HPLC: Purity (214 nm):96.46%; t_(R)=7.81 min.

(R)-6-(5-Methoxylpyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(R)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(70 mg, 0.21 mmol) and3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineafforded the title compound (13 mg, 15%) as a white solid. ¹H NMR (500MHz, MeOD-d₄) δ 8.82 (d, J=1.5 Hz, 1H), 8.47 (d, J=2.5 Hz, 1H), 8.43 (s,1H), 8.03 (t, J=2.0 Hz, 1H), 7.97 (d, J=1.0 Hz, 1H), 4.47-4.43 (m, 1H),4.03 (s, 3H), 2.82 (d, J=1.0 Hz, 3H), 1.31-1.28 (m, 1H), 0.82-0.80 (m,1H), 0.69-0.61 (m, 2H), 0.53-0.48 (m, 1H). LC-MS m/z: 406.0 [M+H]⁺.HPLC: Purity (214 nm): 99.20%; t_(R)=7.67 min.

(S)-6-(5-Methoxylpyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(S)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(50 mg, 0.15 mmol) and 5-methoxylpyridin-3-ylboronic acid afforded thetitle compound (16.3 mg, 27%) as a yellow solid. ¹H NMR (400 MHz,MeOD-d₄) δ 8.82 (s, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 8.02 (s, 1H), 7.96(s, 1H), 4.46-4.42 (m, 1H), 4.03 (s, 3H), 2.82 (s, 3H), 1.31-1.28 (m,1H), 0.82-0.78 (m, 1H), 0.66-0.63 (m, 2H), 0.51-0.49 (m, 1H). LC-MS m/z:406.1 [M+H]⁺. HPLC: Purity (254 nm): 99%; t_(R)=7.69 min.

(R)-6-(6-Methylpyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(R)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(70 mg, 0.21 mmol) and 6-methylpyridin-3-ylboronic acid afforded thetitle compound (34 mg, 41%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 9.14 (d, J=2.0 Hz, 1H), 9.09 (d, J=9.5 Hz, 1H), 8.36 (s, 1H), 8.32(dd, J=8.0 Hz, 2.0 Hz, 1H), 8.04 (d, J=1.0 Hz, 1H), 7.52 (d, J=8.0 Hz,1H), 4.49-4.43 (m, 1H), 2.72 (s, 3H), 2.58 (s, 3H), 1.34-1.21 (m, 1H),0.77-0.54 (m, 3H), 0.41-0.34 (m, 1H). LC-MS m/z: 390.1 [M+H]⁺. HPLCPurity (214 nm): 99.2%; t_(R)=7.75 min.

(S)-6-(6-Methylpyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(S)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.30 mmol) and 6-methylpyridin-3-ylboronic acid afforded thetitle compound (42 mg, 35%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆)δ 9.14 (d, J=2.0 Hz, 1H), 9.09 (d, J=9.0 Hz, 1H), 8.36 (s, 1H), 8.32(dd, J=7.5 Hz, 2.5 Hz, 1H), 8.04 (s, 1H), 7.52 (d, J=8.0 Hz, 1H),4.52-4.42 (m, 1H), 2.72 (s, 3H), 2.58 (s, 3H), 1.29-1.22 (m, 1H),0.73-0.67 (m, 1H), 0.65-0.56 (m, 2H), 0.41-0.37 (m, 1H). LC-MS m/z:390.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=7.73 min.

N—((R)-1-Cyclopropyl-2,2,2-trifluoroethyl)-6-(5-isopropyl-2-oxooxazolidin-3-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure G,(R)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(80 mg, 0.24 mmol) and 5-isopropyloxazolidin-2-one afforded the titlecompound (30 mg, 29%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.86(dd, J=15.0 Hz, 9.5 Hz, 1H), 8.26 (s, 1H), 8.13 (dd, J=8.5 Hz, 1.0 Hz,1H), 4.56-4.54 (m, 1H), 4.41-4.17 (m, 2H), 4.01-3.85 (m, 1H), 2.66 (s,3H), 2.02-1.98 (m, 1H), 1.27-1.24 (m, 1H), 1.00 (d, J=6.5 Hz, 3H), 0.93(dd, J=7.0 Hz, 3.0 Hz, 3H), 0.74-0.60 (m, 2H), 0.60-0.54 (m, 1H),0.41-0.36 (m, 1H). LC-MS m/z: 426.1 [M+H]⁺. HPLC: Purity (254 nm): >99%;t_(R)=8.59 min.

N—((S)-1-Cyclopropyl-2,2,2-trifluoroethyl)-6-(5-isopropyl-2-oxooxazolidin-3-yl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure G,(S)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(100 mg, 0.3 mmol) and 5-isopropyloxazolidin-2-one afforded the titlecompound (7 mg, 5%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄) δ 8.34(dd, J=12.5 Hz, 1H), 8.30 (d, J=2.5 Hz, 1H), 4.57-4.54 (m, 1H),4.40-4.28 (m, 2H), 4.08-3.95 (m, 1H), 2.73 (s, 3H), 2.07-2.04 (m, 1H),1.33-1.25 (m, 1H), 1.13 (dd, J=6.5 Hz, 3.5 Hz, 3H), 1.05 (d, J=7.0 Hz,3H), 0.83-0.81 (m, 1H), 0.66-0.64 (m, 2H), 0.53-0.50 (m, 1H). LC-MS m/z:426.1 [M+H]⁺. HPLC Purity (214 nm): 95.8%; t_(R)=8.602 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-8-methyl-6-(1-methyl-1H-benzo[d]imidazol-6-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(R)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(80 mg, 0.24 mmol) and1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazoleafforded the title compound (40 mg, 39%) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆): 9.27 (d, J=9.5 Hz, 1H), 8.37 (s, 1H), 8.36 (s, 1H), 8.31(d, J=1.0 Hz, 1H), 8.13 (d, J=1.5 Hz, 1H), 7.96 (dd, J=8.5 Hz, 2.0 Hz,1H), 7.86 (d, J=8.5 Hz, 1H), 4.56-4.52 (m, 1H), 3.94 (s, 3H), 2.74 (s,3H), 1.34-1.26 (m, 1H), 0.73-0.68 (m, 1H), 0.67-0.56 (m, 2H), 0.45-0.37(m, 1H). LC-MS m/z: 429.2 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=7.14 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-8-methyl-6-(1-methyl-1H-benzo[d]imidazol-6-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(S)-6-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(80 mg, 0.24 mmol) and1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazoleafforded the title compound (45 mg, 43%) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆): 9.27 (d, J=9.5 Hz, 1H), 8.37 (s, 1H), 8.36 (s, 1H), 8.31(d, J=1.0 Hz, 1H), 8.13 (d, J=1.5 Hz, 1H), 7.96 (dd, J=8.5 Hz, 2.0 Hz,1H), 7.86 (d, J=8.5 Hz, 1H), 4.56-4.52 (m, 1H), 3.94 (s, 3H), 2.74 (s,3H), 1.34-1.26 (m, 1H), 0.73-0.68 (m, 1H), 0.67-0.56 (m, 2H), 0.45-0.37(m, 1H). LC-MS m/z: 429.2 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=7.16 min.

(S)-6-(2-Cyano-5-fluorophenyl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(S)-6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(70 mg, 0.23 mmol) and (2-cyano-5-fluorophenyl)boronic acid afforded thetitle compound (4.7 mg, 5%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.67 (d, J=9.0 Hz, 1H), 8.45 (s, 1H), 8.26 (dd, J=8.5 Hz, 5.5 Hz, 1H),7.97 (dd, J=9.5 Hz, 2.5, 1H), 7.87 (s, 1H), 7.70 (td, J=8.5 Hz, 2.5 Hz,1H), 5.05-4.99 (m, 1H), 2.73 (s, 3H), 1.43 (d, J=7.0 Hz, 3H). LC-MS m/z:392.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.18 min.

(S)-6-(2-Cyano-3-fluorophenyl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(S)-6-chloro-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(61.2 mg, 0.2 mmol) and (2-cyano-3-fluorophenyl)boronic acid affordedthe title compound (18 mg, 23%) as a white solid. ¹H NMR (500 MHz,MeOD-d₄) (8.49 (s, 1H), 7.99-7.95 (m, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.79(s, 1H), 7.66-7.63 (t, J=8.5 Hz, 1H), 5.06-5.03 (m, 1H), 2.83 (s, 3H),1.54 (d, J=7.5 Hz, 3H). LC-MS m/z: 392.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.15 min.

(S)-6-(2-Cyano-6-fluorophenyl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide

To a solution of(S)-6-(2-carbamoyl-6-fluorophenyl)-8-methyl-N-(1,1,1-trifluoropropan-2-yl)imidazo[1,2-b]pyridazine-3-carboxamide(50 mg, 0.30 mmol) in DMF (2 mL) was added SOCl₂ (90 mg, 0.90 mmol)dropwise at 0° C. The mixture was stirred at 0° C. for 2 h then dilutedwith DCM (20 mL), washed with sat. NaHCO₃ (10 mL) and brine (10 mL) anddried over anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by reversed phase HPLC to give the title compound (19.4 mg,40%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (d, J=9.0 Hz,1H), 8.46 (s, 1H), 8.04-8.02 (m, 1H), 7.93-7.85 (m, 2H), 7.76 (d, J=1.5Hz, 1H), 4.99-4.95 (m, 1H), 2.74 (s, 3H), 1.39 (d, J=7.0 Hz 3H). LC-MSm/z: 392.0 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=7.85 min.

(S)-6-(2-Cyano-3-fluorophenyl)-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(S)-6-chloro-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(70 mg, 0.25 mmol) and (2-cyano-3-fluorophenyl)boronic acid afforded thetitle compound (26 mg, 29%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.49 (d, J=8.0 Hz, 1H), 8.35 (s, 1H), 8.06-8.01 (m, 1H), 7.93 (d,J=7.5 Hz, 1H), 7.83 (s, 1H), 7.82 (t, J=9.0 Hz, 1H), 3.58-3.55 (m, 1H),2.74 (s, 3H), 1.28 (d, J=6.5 Hz, 3H), 1.08-1.06 (m, 1H), 0.46-0.44 (m,1H), 0.38-0.33 (m, 2H), 0.32-0.27 (m, 1H). LC-MS m/z: 364.0 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=7.83 min.

(S)-6-(2-Cyano-5-fluorophenyl)-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

Following general procedure D,(S)-6-chloro-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(50 mg, 0.18 mmol) and (2-cyano-5-fluorophenyl)boronic acid afforded thetitle compound (17.2 mg, 24%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.50 (d, J=7.5 Hz, 1H), 8.36 (s, 1H), 8.27 (dd, J=9.0 Hz, 5.5Hz, 1H), 8.01 (dd, J=9.5 Hz, 2.5 Hz, 1H), 7.85 (d, J=1.0 Hz, 1H), 7.71(td, J=8.5 Hz, 2.5 Hz, 1H), 3.67-3.50 (m, 1H), 2.73 (s, 3H), 1.28 (d,J=6.5 Hz, 3H), 1.14-1.03 (m, 1H), 0.48-0.43 (m, 1H), 0.40-0.22 (m, 3H).LC-MS m/z: 364.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.14 min.

(S)-6-(3-Cyano-5-methylfuran-2-yl)-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide

A mixture of(S)-6-chloro-N-(1-cyclopropylethyl)-8-methylimidazo[1,2-b]pyridazine-3-carboxamide(28 mg, 0.10 mmol), 5-methyl-2-(tributylstannyl)furan-3-carbonitrile (48mg, 0.12 mmol), Pd(PPh₃)₄ (12 mg, 0.01 mmol) and CuBr (1 mg, 0.01 mmol)in dioxane (1 mL) was heated to 100° C. under N₂ and stirred for 2 h.The reaction mixture was then cooled to RT, filtered and the filter cakewashed with EA/Et₂O. The cake was dissolved in MeOH and concentrated andthe resulting solid was triturated with DCM/Et₂O to give the titlecompound (8.4 mg, 24%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.34-8.33 (m, 1H), 7.78 (s, 1H), 6.95 (s, 1H), 3.54-3.47 (m, 1H), 2.72(s, 3H), 2.48 (s, 3H), 1.35 (d, J=6.4 Hz, 3H), 1.29-1.23 (m, 1H),0.51-0.24 (m, 4H). LC-MS m/z: 350.2 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.34 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-2-(3-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2-(3-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acid(80 mg, 0.30 mmol) and (R)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (19 mg, 16%) as a white solid.¹H NMR (500 MHz, DMSO-d₆) δ 9.31 (d, J=9.2 Hz, 1H), 7.98 (d, J=8.0 Hz,1H), 7.94 (d, J=10.5 Hz, 1H), 7.88 (s, 1H), 7.65 (q, J=7.5 Hz, 1H), 7.60(s, 1H), 7.44 (td, J=8.5 Hz, 2.0 Hz, 1H), 4.30-4.26 (m, 1H), 2.64 (s,3H), 1.37-1.33 (m, 1H), 0.72-0.64 (m, 1H), 0.63-0.61 (m, 1H), 0.58-0.55(m, 1H), 0.38-0.35 (m, 1H). LC-MS m/z: 393.1 [M+H]⁺. HPLC: Purity (254nm): >99%; t_(R)=8.83 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-2-(3-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2-(3-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acid(57 mg, 0.21 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (16 mg, 19%) as a white solid.¹H NMR (500 MHz, DMSO-d₆) δ 9.31 (d, J=9.5 Hz, 1H), 7.98 (d, J=8.0 Hz,1H), 7.94 (d, J=10.5 Hz, 1H), 7.88 (s, 1H), 7.65 (dd, J=14.0, 8.0 Hz,1H), 7.61 (s, 1H), 7.45 (td, J=8.5 Hz, 2.0 Hz, 1H), 4.32-4.24 (m, 1H),2.64 (s, 3H), 1.38-1.31 (m, 1H), 0.73-0.68 (m, 1H), 0.65-0.60 (m, 1H),0.58-0.53 (m, 1H), 0.40-0.32 (m, 1H). LC-MS m/z: 393.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=9.01 min.

2-(3-Fluorophenyl)-4-methyl-N-(1,1,1-trifluorobut-3-yn-2-yl)imidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2-(3-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acid(100 mg, 0.37 mmol) and 1,1,1-trifluorobut-3-yn-2-amine hydrochlorideafforded the title compound (23 mg, 16%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 9.74 (d, J=9.5 Hz, 1H), 8.00-7.94 (m, 2H), 7.91 (s, 1H),7.68-7.64 (m, 1H), 7.64 (s, 1H), 7.46 (td, J=8.5 Hz, 2.5 Hz, 1H),6.02-5.97 (m, 1H), 3.83 (d, J=2.5 Hz, 1H), 2.65 (s, 3H). LC-MS m/z:377.1 [M+H]⁺. HPLC: Purity (254 nm): 90%; t_(R)=8.45 min.

2-(3-Methoxyphenyl)-4-methyl-N-(1,1,1-trifluorobut-3-yn-2-yl)imidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2-(3-methoxyphenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acid(45 mg, 0.16 mmol) and 1,1,1-trifluorobut-3-yn-2-amine afforded thetitle compound (26.6 mg, 49%) as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.77 (d, J=9.2 Hz, 1H), 7.91 (s, 1H), 7.70 (d, J=8.4 Hz, 1H),7.65 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.18 (dd,J=8.4 Hz, 1.6 Hz, 1H), 6.05-6.02 (m, 1H), 3.88 (s, 3H), 3.85 (d, J=2.4Hz, 1H), 2.65 (s, 3H). LC-MS m/z: 389.0 [M+H]⁺. HPLC: Purity (214 nm):97.8%; t_(R)=8.39 min.

(S)-2-(5-Chloropyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide

A mixture of ZnCN₂ (2.34 g, 20.0 mmol), DPPF (554.0 mg, 1.0 mmol),Pd₂(dba)₃ (457.0 mg, 0.50 mmol) and 6-chloro-5-methylpyridazin-3(2H)-one(1.40 g, 10.0 mmol) in DMF (20 mL) was heated at 100° C. for 5 h. Thereaction mixture was diluted with EA/H₂O and the organic layer wasseparated, washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo, and the residue was purified byflash chromatography on silica (PE:EA=1:1) to afford4-methyl-6-oxo-1,6-dihydropyridazine-3-carbonitrile (1.06 g, 73%) as awhite solid. LC-MS m/z: 136.1 [M+H]⁺. Purity (214 nm): 74%; t_(R)=0.87min.

To a stirred solution of4-methyl-6-oxo-1,6-dihydropyridazine-3-carbonitrile (1.06 g, 7.85 mmol)in MeOH (40 ml) at RT was added 5% Pd/C (100 mg) and 6N HCl (2.62 mL,15.70 mmol) in MeOH (40 mL). The resulting black solution was stirred atRT for 2 h under a H, atmosphere. The crude reaction mixture was elutedthrough a short plug of celite (MeOH followed by DCM) and the organicfraction was concentrated to afford6-(aminomethyl)-5-methylpyridazin-3(2H)-one hydrochloride (790 mg, 58%)as a white solid. LC-MS m/z: 140.2 [M+H]⁺. Purity (214 nm): 100%;t_(R)=0.45 min.

To a suspension of 6-(aminomethyl)-5-methylpyridazin-3(2H)-onehydrochloride (790 mg, 4.49 mmol) in anhydrous THF (80 mL) at 0° C. wasadded ethyl 2-chloro-2-oxoacetate (733 mg, 5.39 mmol) followed by NEt₃(3.3 mL, 22.45 mmol). The reaction mixture was slowly warmed to ambienttemperature. After 18 h, the mixture was concentrated and the residuewas purified by flash chromatography on silica (PE:EA=1:3) to affordethyl2-(((4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)amino)-2-oxoacetate(430 mg, 40%) as a white solid. LC-MS m/z: 240.1 [M+H]⁺. Purity (214nm): 85%; t_(R)=1.10 min.

A stirred mixture of ethyl2-(((4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)amino)-2-oxoacetate(430 mg, 1.80 mmol) and POCl₃ (10 mL) was heated at 100° C. for 3 h. Thereaction mixture was cooled to RT and quenched with sat. NaHCO₃ (50 mL)at 0° C. The mixture was extracted with DCM (100 mL×3) and the organiclayer was washed with brine (50 mL), dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo, and the residue waspurified by silica gel column chromatography (PE:EA=1:1) to afford ethyl2-chloro-4-methylimidazo[1,5-b]pyridazine-7-carboxylate (202 mg, 47%) asa yellow solid. LC-MS m/z: 240.1 [M+H]⁺. Purity (214 nm): 100%;t_(R)=1.54 min.

Following general procedure D, ethyl2-chloro-4-methylimidazo[1,5-b]pyridazine-7-carboxylate (190 mg, 0.80mmol) and (5-chloropyridin-3-yl)boronic acid afforded ethyl2-(5-chloropyridin-3-yl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylate(70 mg, 30%) as a white solid. LC-MS m/z: 317.0 [M+H]⁺. Purity (214 nm):96%; t_(R)=1.53 min.

Following general procedure B, ethyl2-(5-chloropyridin-3-yl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylate(70 mg, 0.22 mmol) afforded2-(5-chloropyridin-3-yl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylicacid (63 mg, 100%) as a white solid. LC-MS m/z: 289.1 [M+H]⁺. Purity(214 nm): 66%; t_(R)=1.19 min.

Following general procedure A,2-(5-chloropyridin-3-yl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylicacid (63 mg, 0.22 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (34 mg, 49%) as a white solid.¹H NMR (500 MHz, DMSO-d₆) δ 9.28 (d, J=8.0 Hz, 1H), 9.26 (s, 1H), 8.45(d, J=2.0 Hz, 1H), 8.60 (t, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.69 (s, 1H),4.27-4.24 (m, 1H), 2.65 (s, 3H), 1.36-1.34 (m, 1H), 0.71-0.70 (m, 1H),0.64-0.62 (m, 1H), 0.57-0.54 (m, 1H), 0.37-0.32 (m, 1H). LC-MS m/z:410.1, 412.1 [M+H]⁺. HPLC: Purity (214 nm): 94%; t_(R)=8.30 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-4-methyl-2-(3-methylisothiazol-5-yl)imidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure F, ethyl2-chloro-4-methylimidazo[1,5-b]pyridazine-7-carboxylate (100 mg, 0.417mmol) and 3-methyl-5-(tributylstannyl)isothiazole (325 mg, 0.85 mmol)afforded ethyl4-methyl-2-(3-methylisothiazol-5-yl)imidazo[1,5-b]pyridazine-7-carboxylate(30 mg, 12%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (s, 1H), 7.91 (s, 1H),7.57 (d, J=0.8 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 2.62 (d, J=0.8 Hz, 3H),2.52 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). LC-MS m/z: 303.1 [M+H]⁺.t_(R)=1.21 min.

Following general procedure B, ethyl4-methyl-2-(3-methylisothiazol-5-yl)imidazo[1,5-b]pyridazine-7-carboxylate(30 mg, 0.1 mmol) afforded4-methyl-2-(3-methylisothiazol-5-yl)imidazo[1,5-b]pyridazine-7-carboxylicacid (27 mg, 99%) as a brown solid. LC-MS (m/z): 275.2 [M+H]⁺, Purity(214 nm): 71%; t_(R)=1.46 min.

Following general procedure A,4-methyl-2-(3-methylisothiazol-5-yl)imidazo[1,5-b]pyridazine-7-carboxylicacid (27 mg, 0.1 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (6.4 mg, 16%) as a yellowsolid. ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (d, J=9.0 Hz, 1H), 8.03 (s, 1H),7.92 (s, 1H), 7.55 (s, 1H), 4.28-4.23 (m, 1H), 2.64 (s, 3H), 2.52 (s,3H), 1.39-1.34 (m, 1H), 0.76-0.52 (m, 3H), 0.41-0.31 (m, 1H). LC-MS m/z:396.0 [M+H]⁺. HPLC Purity (214 nm): 97%; t_(R)=8.34 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-2-(3-isopropyl-2-oxoimidazolidin-1-yl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure B, ethyl2-chloro-4-methylimidazo[1,5-b]pyridazine-7-carboxylate (600 mg, 2.5mmol) afforded 2-chloro-4-methylimidazo[1,5-b]pyridazine-7-carboxylicacid (530 mg, 100%) as a brown solid. LC-MS (m/z): 212.1 [M+H]⁺, Purity(214 nm): 65%; t_(R)=0.76 min.

Following general procedure A,2-chloro-4-methylimidazo[1,5-b]pyridazine-7-carboxylic acid (530 mg, 2.5mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochlorideafforded(S)-2-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide(300 mg, 32%) as a yellow solid. LC-MS (m/z): 333.0 [M+H]⁺, Purity (214nm): 71%; t_(R)=1.34 min.

Following general procedure G,(S)-2-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide(50 mg, 0.15 mmol) and 1-isopropylimidazolidin-2-one afforded the titlecompound (3.2 mg, 5%) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.74(d, J=9.5 Hz, 1H), 8.12 (s, 1H), 8.61 (s, 1H), 4.48-4.40 (m, 1H),4.33-4.27 (m, 1H), 4.09-4.00 (m, 3H), 3.55 (t, J=7.5 Hz, 2H), 2.55 (s,3H), 2.40 (d, J=6.5 Hz, 6H), 1.16-1.09 (m, 1H), 0.77-0.71 (m, 1H),0.62-0.53 (m, 3H). LC-MS m/z: 425.0 [M+H]⁺, HPLC: Purity (214 nm): 98%;t_(R)=8.27 min.

(S)-2-(5-Carbamoylfuran-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure F, ethyl2-chloro-4-methylimidazo[1,5-b]pyridazine-7-carboxylate (100 mg, 0.417mmol) and 5-(tributylstannyl)furan-2-carbonitrile afforded ethyl2-(5-cyanofuran-2-yl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylate (40mg, 32%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄) δ 7.86 (s, 1H),7.60-7.52 (m, 2H), 7.44 (d, J=1.0 Hz, 1H), 4.54 (q, J=7.0 Hz, 2H), 2.70(d, J=1.0 Hz, 3H), 1.50 (t, J=7.0 Hz, 3H). LC-MS m/z: 297.1 [M+H]⁺,t_(R)=1.22 min.

Following general procedure B, ethyl2-(5-cyanofuran-2-yl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylate (40mg, 0.135 mmol) afforded2-(5-carbamoylfuran-2-yl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylicacid (30 mg, 77%) as a brown solid. LC-MS (m/z): 287.1 [M+H]⁺, Purity(254 nm): 80%, t_(R)=1.26 min.

Following general procedure A,2-(5-carbamoylfuran-2-yl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylicacid (30 mg, 0.1 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (20 mg, 50%) as a yellowsolid. ¹H NMR (500 MHz, MeOD-d₄) δ 7.86 (s, 1H), 7.57 (s, 1H), 7.46 (d,J=4.0 Hz, 1H), 7.35 (d, J=3.5 Hz, 1H), 4.44-4.32 (m, 1H), 2.71 (s, 3H),1.44-1.40 (m, 1H), 0.86-0.80 (m, 1H), 0.74-0.60 (m, 2H), 0.53-0.50 (m,1H). LC-MS m/z: 408.0 [M+H]⁺. HPLC Purity (214 nm): 94%; t_(R)=6.76 min.

(S)-2-(5-Cyanofuran-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide

To a solution of(S)-2-(5-carbamoylfuran-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide(10 mg, 0.025 mmol) in DMF (0.5 mL) was added SOCl₂ (7.4 mg, 0.0625mmol). The mixture was stirred at 0° C. for 1 h, concentrated in vacuoand then purified by preparative HPLC to give the title compound (7.8mg, 80%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄) δ 7.90 (s, 1H),7.58 (d, J=4.0 Hz, 2H), 7.56 (d, J=3.5 Hz, 2H), 7.44 (d, J=1.0 Hz, 1H),4.53-4.40 (m, 1H), 2.72 (d, J=1.0 Hz, 3H), 1.40-1.35 (m, 1H), 0.83-0.79(m, 1H), 0.72-0.69 (m, 1H), 0.69-0.58 (m, 2H). LC-MS m/z: 390.0 [M+H]⁺.HPLC Purity (214 nm): 98%; t_(R)=8.16 min.

(S)-2-(2-Cyano-4-fluorophenyl)-N-(1-cyclopropylethyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure D, ethyl2-chloro-4-methylimidazo[1,5-b]pyridazine-7-carboxylate (200 mg, 0.84mmol) and (2-cyano-4-fluorophenyl)boronic acid afforded ethyl2-(2-cyano-4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylate(70 mg, 26%) as a yellow solid. LC-MS m/z: 325.1 (M+1)+. LC-MS Purity(214 nm): 84%; t_(R)=1.42 min.

Following general procedure B, ethyl2-(2-cyano-4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylate(60 mg, 0.19 mmol) afforded2-(2-cyano-4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylicacid (10 mg, 15%) as a white solid. LC-MS m/z: 297.1 (M+1)^(|). LC-MSPurity (254 nm): 59%; t_(R)=1.03 min.

Following general procedure A,2-(2-cyano-4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylicacid (40 mg, 0.14 mmol) and (S)-1-cyclopropylethan-1-amine afforded thetitle compound (14.0 mg, 27%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.68 (d, J=8.0 Hz, 1H), 8.18 (dd, J=9.0 Hz, 2.5 Hz, 1H), 8.06(dd, J=9.0 Hz, 5.0 Hz, 1H), 7.92 (s, 1H), 7.88 (td, J=9.0 Hz, 3.0 Hz,1H), 7.29 (s, 1H), 3.55-3.51 (m, 1H), 2.65 (s, 3H), 1.27 (d, J=6.5 Hz,3H), 1.08-1.05 (m, 1H), 0.45-0.43 (m, 1H), 0.36-0.30 (m, 2H), 0.26-0.24(m, 1H). LC-MS m/z: 363.9 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=7.83 min.

(S)-2-(2-Cyano-4-fluorophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxamide

Following general procedure A,2-(2-cyano-4-fluorophenyl)-4-methylimidazo[1,5-b]pyridazine-7-carboxylicacid (10 mg, 0.034 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (2.8 mg, 19%) as a yellowsolid. ¹H NMR (500 MHz, MeOD-d₄) δ 8.04 (dd, J=8.5 Hz, 5.0 Hz, 1H), 7.96(s, 1H), 7.88 (dd, J=8.5 Hz, 3.0 Hz, 1H), 7.71 (td, J=8.5 Hz, 3.0 Hz,1H), 7.31 (d, J=1.0 Hz, 1H), 4.32-4.29 (m, 1H), 2.75 (s, 3H), 1.39-1.34(m, 1H), 0.79-0.76 (m, 1H), 0.65-0.59 (m, 2H), 0.49-0.46 (m, 1H). LC-MSm/z: 418.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.36 min.

5,7-Dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)isothiazolo[4,5-b]pyridine-3-carboxamide

To a solution of 5-bromo-2,4-dimethylpyridine (12 g, 64.5 mmol) in DCM(200 mL) was added m-CPBA (13.2 g, 77.4 mmol) and the solution wasstirred at RT overnight. The reaction mixture was partitioned betweensat. NaHCO₃ (300 mL) and DCM (200 mL). The organic layer was washed withH₂O (150 mL), brine (150 mL) and dried over anhydrous Na₂SO₄ andconcentrated in vacuo to give 5-bromo-2,4-dimethylpyridine 1-oxide (4.0g, 30%) as a yellow solid. LC-MS m/z: 204.0 [M+H]⁺. LC-MS Purity (214nm): 98%; t_(R)=0.84 min.

A stirred solution of 5-bromo-2,4-dimethylpyridine 1-oxide (6.0 g, 29.7mmol), CNSiMe₃ (9.0 g, 89.1 mmol) and TEA (12.0 g, 118.8 mmol) in CH₃CN(60 mL) was refluxed for 20 h. The solution was concentrated and theresidue was diluted with H₂O (50 mL). The mixture was extracted with DCM(50 mL×2), washed with brine (100 mL) and the combined organic extractswere dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas purified by silica gel chromatography (PE:EA=5:1) to give3-bromo-4,6-dimethylpicolinonitrile (4.0 g, 60%) as a white solid. LC-MSm/z: 213.0 [M+H]⁺. LC-MS Purity (214 nm): 99%; t_(R)=1.23 min.

To a solution of 3-bromo-4,6-dimethylpicolinonitrile (2.4 g, 11.4 mmol)in DMA (10 mL) was added sodium thiomethoxide (4.0 g, 57.0 mmol) and thereaction mixture was heated to 130° C. and stirred for 1 h. The reactionwas quenched with con. HCl (10 mL) at 0° C. and the mixture was stirredat RT overnight. The mixture was concentrated and purified by reversedphase HPLC to give 3,3′-bis(4,6-dimethylpicolinonitrile)disulfide (1.6g, 43%) as a yellow solid. LC-MS m/z: 327.0 [M+H]⁺. LC-MS Purity (214nm): 65%; t_(R)=1.41 min.

A mixture of 3,3′-bis(4,6-dimethylpicolinonitrile)disulfide (370 mg,1.13 mmol) and NaBH₄ (132 mg, 3.47 mmol) in MeCN (20 mL) was stirred atRT overnight. The reaction mixture was acidified with 6N HCl to pH˜5 andextracted with EA (20 mL×3). The combined organic phase was dried overanhydrous Na₂SO₄ and concentrated in vacuo to give3-mercapto-4,6-dimethylpicolinonitrile (256 mg, 69%) as a dark orangesolid. LC-MS m/z: 165.1 [M+H]⁺. t_(R)=1.12 min.

A solution of 3-mercapto-4,6-dimethylpicolinonitrile (372 mg, 2.27 mmol)in EA (25 mL) was stirred at 0° C. for 5 min followed by the addition ofBr₂ (436 mg, 2.73 mmol). The mixture was stirred at RT for 30 min andthen refluxed for 1 h. The reaction was diluted with H₂O (20 mL),extracted with EA (30 mL) and washed with sat. sodium bisulfite (20 mL),dried over anhydrous Na₂SO₄, and concentrated in vacuo to give a residuewhich was purified by silica gel chromatography (DCM:MeOH=1:0 to 10:1)to give 3-bromo-5,7-dimethylisothiazolo[4,5-b]pyridine (240 mg, 44%) asa white solid. LC-MS m/z: 244.9 [M+H]⁺. t_(R)=1.29 min.

To a solution of 3-bromo-5,7-dimethylisothiazolo[4,5-b]pyridine (180 mg,0.74 mmol) in a mixture of TEA (0.52 mL, 3.75 mmol) and MeOH (80 mL) wasadded Pd(dppf)Cl₂.DCM (91 mg, 0.11 mmol). The reaction was heated to 70°C. and stirred for 6 h under 45 atm of CO. Upon completion, the reactionwas cooled to RT and the crude product was concentrated in vacuo andpurified by reversed phase HPLC to give methyl5,7-dimethylisothiazolo[4,5-b]pyridine-3-carboxylate (95 mg, 58%) as awhite solid. LC-MS m/z: 223.1 [M+H]⁺, Purity (214 nm): 93%; t_(R)=1.09min.

To a stirred solution of (1R,4R)-4-(pentyloxy)cyclohexan-1-amine (52 mg,0.28 mmol) in toluene (2 mL) was added AlMe₃ (0.21 mL, 0.42 mmol) at 0°C. The reaction mixture was stirred at RT for 1 h followed by theaddition of a solution of methyl5,7-dimethylisothiazolo[4,5-b]pyridine-3-carboxylate (30 mg, 0.14 mmol)in THF (2 mL). The reaction mixture was heated to 110° C. and stirredfor 40 min. Sat. NH₄Cl (10 mL) was then added and the mixture wasextracted with EA (20 mL). The organic layer was washed with H₂O (5 mL)and brine (5 mL) and concentrated in vacuo to give a residue which waspurified by preparative HPLC to give the title compound (4.2 mg, 8%) asa white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 9.80 (d, J=7.5 Hz, 1H), 7.48(s, 1H), 7.94-7.85 (m, 1H), 3.94-3.85 (m, 1H), 3.40 (t, J=6.5 Hz, 2H),3.34-3.33 (m, 1H), 2.69 (s, 3H), 2.64 (s, 3H), 2.04-1.95 (m, 4H),1.52-1.34 (m, 6H), 1.32-1.25 (m, 4H), 0.88 (t, J=6.5 Hz, 3H). LC-MS m/z:375.9 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=10.39 min.

5,7-Dimethyl-N-(1-phenylpropyl)isothiazolo[4,5-b]pyridine-3-carboxamide

To a stirred solution of 1-phenylpropan-1-amine (61 mg, 0.45 mmol) intoluene (2 mL) was added AlMe₃ (0.27 mL, 0.54 mmol) at 0° C. Thereaction mixture was stirred at RT for 1 h followed by the addition of asolution of methyl 5,7-dimethylisothiazolo[4,5-b]pyridine-3-carboxylate(40 mg, 0.18 mmol) in THF (2 mL). The reaction mixture was heated to110° C. and stirred for 40 min. Sat. NH₄Cl (10 mL) was then added andthe mixture was extracted with EA (20 mL). The organic layer was washedwith H₂O (5 mL), brine (5 mL) and concentrated in vacuo to give aresidue which was purified by reversed-phase HPLC to give the titlecompound (27.5 mg, 47%) as an off white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 10.30 (d, J=8.5 Hz, 1H), 7.50 (s, 1H), 7.45 (d, J=6.5 Hz, 2H), 7.37(t, J=7.5 Hz, 2H), 7.27 (t, J=7.5 Hz, 1H), 5.06 (q, J=7.5 Hz, 1H), 2.71(s, 3H), 2.65 (s, 3H), 1.95-1.87 (m, 2H), 0.95 (t, J=7.0 Hz, 3H). LC-MSm/z: 326.2[M+H]⁺. HPLC: Purity (214 nm): 98%; t_(R)=9.27 min.

5,7-Dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isothiazolo[4,5-b]pyridine-3-carboxamide

To a stirred solution of 1,2,3,4-tetrahydronaphthalen-1-amine (40 mg,0.28 mmol) in toluene (2 mL) was added AlMe₃ (0.21 mL, 0.42 mmol) at 0°C. The reaction mixture was stirred at RT for 1 h followed by theaddition of a solution of methyl5,7-dimethylisothiazolo[4,5-b]pyridine-3-carboxylate (30 mg, 0.14 mmol)in THF (2 mL). The reaction mixture was heated to 110° C. and stirredfor 40 min. Sat. NH₄Cl (10 mL) was then added and the mixture wasextracted with EA (20 mL). The organic layer was washed with H₂O (5 mL),brine (5 mL) and concentrated in vacuo to give a residue which waspurified by reversed-phase HPLC to give the title compound (8 mg, 15%)as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 10.16 (d, J=9.0 Hz, 1H),7.45-7.43 (m, 2H), 7.22-7.14 (m, 3H), 5.34-5.28 (m, 3H), 2.90-2.75 (m,2H), 2.64 (s, 3H), 2.57 (s, 3H), 2.17-2.08 (m, 1H), 1.99-1.86 (m, 3H).LC-MS m/z: 338.0 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=9.45 min.

N-(2,3-Dihydro-1H-inden-5-yl)-5,7-dimethylisothiazolo[4,5-b]pyridine-3-carboxamide

To a stirred solution of 2,3-dihydro-1H-inden-5-amine (40 mg, 0.28 mmol)in toluene (2 mL) was added AlMe₃ (0.21 mL, 0.42 mmol) at 0° C. Thereaction mixture was stirred at RT for 1 h followed by the addition of asolution of methyl 5,7-dimethylisothiazolo[4,5-b]pyridine-3-carboxylate(30 mg, 0.14 mmol) in THF (2 mL). The reaction mixture was heated to110° C. and stirred for 40 min. Sat. NH₄Cl (10 mL) was then added andthe mixture was extracted with EA (20 mL). The organic layer was washedwith H₂O (5 mL), brine (5 mL) and concentrated in vacuo to give aresidue which was purified by reversed-phase HPLC to give the titlecompound (5 mg, 10%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 11.82(s, 1H), 7.77 (s, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.53 (s, 1H), 7.27 (d,J=7.5 Hz, 1H), 2.91 (t, J=7.0 Hz, 2H), 2.86 (t, J=7.0 Hz, 2H), 2.7 (s,3H), 2.67 (s, 3H), 2.08-2.02 (m, 2H). LC-MS m/z: 323.9 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R)=10.14 min.

5,7-Dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)furo[3,2-b]pyridine-3-carboxamide

To a solution of 2-bromo-4,6-dimethylpyridin-3-amine (15 g, 75 mmol) in20% fluoroboric acid (180 mL) was added aq. NaNO₂ (5.7 g, 82.5 mmol, in30 mL) at 0° C. The mixture was stirred at 0° C. for 30 min and thenheated at 110° C. for 30 min. After cooling to RT, the solution wasneutralized with sat. NaHCO₃ to pH˜7 and extracted with DCM (300 mL).The organic layer was concentrated in vacuo and the residue was purifiedby silica gel chromatography (PE:EA=1:1) to give2-bromo-4,6-dimethylpyridin-3-ol (1.7 g, 12%) as a brown solid. LC-MSm/z: 202.0 [M+H]⁺, HPLC: Purity (214 nm): 95%; t_(R)=0.89 min.

A mixture of 2-bromo-4,6-dimethylpyridin-3-ol (1.5 g, 7.46 mmol), ethylpropiolate (730 mg, 7.46 mmol) and 1,4-diazabicyclo[2.2.2]octane (83 mg,0.75 mmol) in DCM (150 mL) was stirred at RT for 30 min. The reactionmixture was concentrated in vacuo and purified by silica gelchromatography (EA) to give ethyl(E)-3-((2-bromo-4,6-dimethylpyridin-3-yl)oxy)acrylate (1.8 g, 80%) as awhite solid. LC-MS m/z: 300.0 [M+H]⁺, HPLC: Purity (214 nm): 95%;t_(R)=1.42 min.

A mixture of ethyl (E)-3-((2-bromo-4,6-dimethylpyridin-3-yl)oxy)acrylate(1.7 g, 5.68 mmol), Pd(PPh₃)₂Cl₂ (400 mg, 0.57 mmol) and KOAc (1.7 g,17.04 mmol) in DMF (100 mL) under N₂ was stirred at 120° C. for 2 h. Thereaction mixture was filtered, concentrated in vacuo and purified bysilica gel chromatography (EA) to give ethyl5,7-dimethylfuro[3,2-b]pyridine-3-carboxylate (500 mg, 40%) as a whitesolid. LC-MS m/z: 220.0 [M+H]⁺, HPLC: Purity (214 nm): 95%; t_(R)=1.21min.

Following general procedure B, ethyl5,7-dimethylfuro[3,2-b]pyridine-3-carboxylate (50 mg, 0.23 mmol)afforded 5,7-dimethylfuro[3,2-b]pyridine-3-carboxylic acid (44 mg, 99%)as a yellow solid. LC-MS m/z: 192.1 [M+H]⁺; t_(R)=0.71 min.

Following general procedure A,5,7-dimethylfuro[3,2-b]pyridine-3-carboxylic acid (30 mg, 0.16 mmol) and(1R,4R)-4-(pentyloxy)cyclohexan-1-amine afforded the title compound (4.8mg, 9%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.75 (s, 1H),8.69 (d, J=7.5 Hz, 1H), 7.21 (s, 1H), 3.85-3.83 (m, 1H), 3.39 (1, J=6.5Hz, 2H), 3.32 (s, 3H), 2.88 (m, 1H), 2.58 (s, 3H), 2.00-1.95 (m, 4H),1.49-1.45 (m, 2H), 1.42-1.33 (m, 4H), 1.31-1.24 (m, 4H), 0.87 (t, J=7.0Hz, 3H). LC-MS m/z: 359.1 [M+H]⁺. HPLC: Purity (214 nm)): 95%;t_(R)=11.26 min.

5,7-Dimethyl-N-(1-phenylpropyl)furo[3,2-b]pyridine-3-carboxamide

Following general procedure A,5,7-dimethylfuro[3,2-b]pyridine-3-carboxylic acid (30 mg, 0.16 mmol) and1-phenylpropan-1-amine afforded the title compound (4.8 mg, 10%) as awhite solid. ¹H NMR (500 MHz, DMSO-d₆) δ 9.27 (d, J=8.0 Hz, 1H), 8.77(s, 1H), 7.42-7.34 (M, 4H), 7.29-7.25 (m, 2H), 5.03 (q, J=8.0 Hz, 1H),2.62 (s, 3H), 2.51 (s, 3H), 1.92-1.85 (m, 2H), 0.91 (t, J=7.5 Hz, 3H).LC-MS m/z: 309.1 [M+H]⁺. HPLC: Purity (214 nm): 90%; t_(R)=10.14 min.

5,7-Dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)furo[3,2-b]pyridine-3-carboxamide

Following general procedure A,5,7-dimethylfuro[3,2-b]pyridine-3-carboxylic acid (30 mg, 0.16 mmol) and1,2,3,4-tetrahydronaphthalen-1-amine afforded the title compound (6.6mg, 12%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 9.05 (d, J=8.5Hz, 1H), 8.84 (s, 1H), 7.33 (d, J=7.0 Hz, 1H), 7.21-7.14 (m, 4H), 5.29(q, J=7.5 Hz, 1H), 2.94-2.73 (m, 1H), 2.47 (s, 3H), 1.15-1.06 (m, 1H),1.97-1.80 (m, 3H). LC-MS m/z: 321.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=10.14 min.

N-(2,3-Dihydro-1H-inden-5-yl)-5,7-dimethylfuro[3,2-b]pyridine-3-carboxamide

Following general procedure A,5,7-dimethylfuro[3,2-b]pyridine-3-carboxylic acid (30 mg, 0.16 mmol) and2,3-dihydro-1H-inden-5-amine afforded the title compound (9.3 mg, 15%)as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 10.75 (s, 1H), 8.92 (s,1H), 7.68 (s, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.25 (d, J=8.0Hz, 1H), 2.90 (t, J=7.0 Hz, 2H), 2.85 (t, J=7.0 Hz, 2H), 2.68 (s, 3H),2.53 (s, 3H), 2.05-2.02 (m, 2H). LC-MS m/z: 307.1 [M+H]⁺. HPLC: Purity(214 nm)): 95%; t_(R)=10.93 min.

5,7-Dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)isoxazolo[4,5-b]pyridine-3-carboxamide

A solution of 4,6-dimethyl-3-nitropyridin-2(1H)-one (9.0 g, 53.5 mmol)in POCl₃ (50 mL) was stirred at 100° C. for 5 h and then cooled andconcentrated in vacuo to give a residue which was dissolved in DCM (50mL). Saturated NaHCO₃ was added dropwise at 0° C. to pH >7. The organicphase was separated, dried over anhydrous Na₂SO₄, and filtered. Thefiltrate was concentrated in vacuo and triturated with PE to afford2-chloro-4,6-dimethyl-3-nitropyridine (9.0 g, 90%) as a brown solid.LC-MS m/z: 187.1 [M+H]⁺. Purity (214 nm): 96%; t_(R)=1.76 min.

To a stirred solution of NaH (1.77 g, 44.33 mmol) in THF (60 mL) wasadded diethyl malonate (12.9 g, 80.6 mmol) at 0° C. and the solution wasstirred at RT. After 1 h, a solution of2-chloro-4,6-dimethyl-3-nitropyridine (7.5 g, 40.3 mmol) in THF (10 mL)was added and the reaction mixture was stirred at 75° C. for 3 d. Aftercooling to RT sat. NaHCO₃ (30 mL) and DCM (50 mL) was added and theorganic layer was washed with H₂O (10 mL) and brine (10 mL). Thecombined organic phase was dried over anhydrous Na₂SO₄, concentrated invacuo and purified by silica gel chromatography (PE:EA=3:1) to givediethyl 2-(4,6-dimethyl-3-nitropyridin-2-yl)malonate (4.2 g, 33%) as ayellow oil. LC-MS m/z: 311.2 [M+H]⁺. Purity (214 nm): 88%; t_(R)=1.94min.

The solution of diethyl 2-(4,6-dimethyl-3-nitropyridin-2-yl)malonate(4.2 g, 13.5 mmol), LiCl (8.53 g, 20.32 mmol) and H₂O (487 mg, 2.70mmol) in DMSO (10 mL) was stirred at 100° C. for 2 d. The reactionmixture was cooled to RT, H₂O (20 mL) was added, and the solutionextracted with EA (10 ml×5) and washed with brine (10 mL). The combinedorganic phase was dried over anhydrous Na₂SO₄, concentrated in vacuo andpurified by silica gel chromatography (PE:EA=5:1) to give ethyl2-(4,6-dimethyl-3-nitropyridin-2-yl)acetate (3.38 g 92%) as a clear oil.LC-MS m/z: 239.2 [M+H]⁺. Purity (254 nm): 79%; t_(R)=1.83 min.

A solution of NaH (0.57 g, 14.2 mmol) in EtOH (20 mL) was stirred at RTfor 30 min followed by the addition of ethyl2-(4,6-dimethyl-3-nitropyridin-2-yl)acetate (3.38 g, 14.2 mmol) andisopentyl nitrite (0.17 g, 14.2 mmol). The reaction was stirredovernight at RT, then concentrated in vacuo and EA (20 mL) was added.The organic layer was washed with sat. NaHCO₃ (20 mL), brine (10 mL),dried over anhydrous Na₂SO₄, concentrated in vacuo and purified bytriturating with diethyl ether (20 mL) to give ethyl2-(4,6-dimethyl-3-nitropyridin-2-yl)-2-(hydroxyimino)acetate (1.8 g,47%) as a yellow solid. LC-MS m/z: 268.1 [M+H]⁺. Purity (214 nm): 97%;t_(R)=1.65 min.

To a stirred solution of ethyl2-(4,6-dimethyl-3-nitropyridin-2-yl)-2-(hydroxyimino)acetate (1.8 g,6.74 mmol) in DMF (10 mL) was added NaH (0.27 g, 6.74 mmol) and thesolution was stirred at 130° C. for 30 min. The solution was cooled toRT and then EA (50 mL) was added. The organic layer was washed with H₂O(10 mL×5), brine (10 mL), dried over Na₂SO₄, concentrated in vacuo andpurified by silica gel chromatography (PE:EA=1:1) to give ethyl5,7-dimethylisoxazolo[4,5-b]pyridine-3-carboxylate (986 mg, 66%) as ayellow solid. LC-MS m/z: 221.2 [M+H]⁺. Purity (254 nm): >99%;t_(R)=1.77.

A solution of ethyl 5,7-dimethylisoxazolo[4,5-b]pyridine-3-carboxylate(80 mg, 0.36 mmol), (1R,4R)-4-(pentyloxy)cyclohexan-1-amine (241 mg,1.09 mmol) and DIPEA (140 mg, 1.09 mmol) in EtOH (3 mL) was stirred at85° C. for 2 d. The reaction mixture was cooled, concentrated in vacuoand purified by preparative HPLC to give the title compound (43 mg, 33%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (d, J=8.0 Hz, 1H),7.50 (s, 1H), 3.89-3.82 (m, 1H), 3.40 (t, J=6.8 Hz, 2H), 3.28-3.23 (m,1H), 2.62 (s, 3H), 2.57 (s, 3H), 1.99-1.95 (m, 4H), 1.51-1.39 (m, 4H),1.37-1.26 (m, 6H), 0.87 (t, J=6.8 Hz, 3H). LC-MS m/z: 360.3 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=10.28 min.

5,7-Dimethyl-N-(1-phenylpropyl)isoxazolo[4,5-b]pyridine-3-carboxamide

A solution of ethyl 5,7-dimethylisoxazolo[4,5-b]pyridine-3-carboxylate(100 mg, 0.45 mmol), 1-phenylpropan-1-amine (614 mg, 4.54 mmol) andDIPEA (583 mg, 4.54 mmol in EtOH (2 mL) was stirred at 85° C. overnight.The reaction mixture was cooled, concentrated in vacuo and purified bypreparative HPLC to give the title compound (79 mg, 56%) as a whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ 9.44 (d, J=8.5 Hz, 1H), 7.51 (d,J=0.5 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 7.37 (t, J=7.5 Hz, 2H), 7.28 (t,J=7.5 Hz, 1H), 5.02 (q, 0.1=8.5 Hz, 1H), 2.63 (s, 3H), 2.58 (d, J=1.0Hz, 3H), 1.91-1.83 (m, 2H), 0.94 (t, J=7.0 Hz, 3H). LC-MS m/z: 310.1[M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=9.31 min.

5,7-Dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isoxazolo[4,5-b]pyridine-3-carboxamide

A solution of ethyl 5,7-dimethylisoxazolo[4,5-b]pyridine-3-carboxylate(120 mg, 0.55 mmol) and 1,2,3,4-tetrahydronaphthalen-1-amine (614 mg,4.36 mmol) in EtOH (3 mL) was stirred at 85° C. for 36 h. The reactionmixture was cooled, concentrated in vacuo and purified by preparativeHPLC to give the title compound (112.8 mg, 64%) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 9.32 (d, J=8.4 Hz, 1H), 7.49 (s, 1H), 7.39-7.36 (m,1H), 7.23-7.13 (m, 3H), 5.33-5.28 (m, 1H), 2.86-2.74 (m, 2H), 2.56 (s,6H), 2.13-2.08 (m, 1H), 1.97-1.84 (m, 3H). LC-MS m/z: 322.1 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=9.43 min.

N-(2,3-Dihydro-1H-inden-5-yl)-5,7-dimethylisoxazolo[4,5-b]pyridine-3-carboxamide

A solution of 2,3-dihydro-1H-inden-5-amine (60 mg, 0.45 mmol) and n-BuLi(0.18 mL, 0.45 mmol) in THF (2 mL) was stirred at −78° C. for 10 min andthen added to a solution of ethyl5,7-dimethylisoxazolo[4,5-b]pyridine-3-carboxylate (50 mg, 0.23 mmol) inTHF (2 mL) at −78° C. The reaction was stirred at −78° C. for 1 h. Thensaturated NH₄Cl (5 mL) solution was added and the mixture was extractedwith DCM (30 mL). The organic layer was washed with H₂O (5 mL) and brine(5 mL), concentrated in vacuo and purified by preparative HPLC to givethe title compound (21.6 mg, 26%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.90 (s, 1H), 7.70 (s, 1H), 7.54 (s, 1H), 7.50 (d, J=8.4 Hz,1H), 7.26 (d, J=8.0 Hz, 1H), 2.92-2.84 (m, 4H), 2.66 (s, 3H), 2.61 (s,3H), 2.08-2.01 (m, 2H). LC-MS m/z: 308.2 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=9.99 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5,7-dimethylisoxazolo[4,5-b]pyridine-3-carboxamide

To a stirred solution of 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride (191 mg, 1.09 mmol) in toluene (2 mL) was added AlMe₃(0.68 mL, 1.36 mmol) at 0° C. and the mixture was stirred at RT for 1 h.Then a solution of ethyl5,7-dimethylisoxazolo[4,5-b]pyridine-3-carboxylate (60 mg, 0.27 mmol) inTHF (1 mL) was added and the reaction was stirred at 110° C. for 30 min.Saturated NH₄Cl (10 mL) was added and the mixture was extracted with EA(20 mL). The organic layer was washed with H₂O (5 mL) and brine (5 mL),concentrated in vacuo and purified by preparative HPLC to give the titlecompound (37 mg, 37%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 9.64(d, J=9.5 Hz, 1H), 7.52 (s, 1H), 4.33 (q, J=8.5 Hz, 1H), 2.63 (s, 3H),2.59 (s, 3H), 1.30-1.24 (m, 1H), 0.73-0.56 (m, 3H), 0.44-0.39 (m, 1H).LC-MS m/z: 314.2 [M+H]⁺. HPLC: Purity (214 nm): 97%; t_(R)=8.97 min.

N-(2-Cyclopropylpropan-2-yl)-5,7-dimethylisoxazolo[4,5-b]pyridine-3-carboxamide

To a stirred solution of 2-cyclopropylpropan-2-amine (67 mg, 0.68 mmol)in toluene (2 mL) was added AlMe₃ (0.45 mL, 0.91 mmol) at 0° C. and themixture was stirred at RT for 1 h. Then a solution of ethyl5,7-dimethylisoxazolo[4,5-b]pyridine-3-carboxylate (50 mg, 0.23 mmol) inTHF (1 mL) was added and the reaction was stirred at 110° C. for 30 min.Saturated NH₄Cl (10 mL) solution was added and the mixture was extractedwith EA (20 mL). The organic layer was washed with H₂O (5 mL) and brine(5 mL), concentrated in vacuo and purified by silica gel chromatography(PE:EA=1:2) to give the title compound (15 mg, 25%) as a white solid. ¹HNMR (500 MHz, DMSO-d₆) δ 8.75 (s, 1H), 7.52 (s, 1H), 2.64 (s, 3H), 2.58(s, 3H), 1.38 (s, 6H), 1.26-1.23 (m, 1H), 0.48-0.47 (m, 4H). LC-MS m/z:274.2 [M+H]⁺. HPLC: Purity (214 nm): 97%; t_(R)=9.26 min.

Example 3—Biological Activity Evaluation

The ability of exemplary compounds to activate glucocerebrosidase(Gcase) was measured. Experimental procedures and results are providedbelow.

Part I: Assay Procedure

A 484 μL aliquot of a 1.0 mg/mL solution of phosphatidylserine (PS)(Sigma P7769) in chloroform was evaporated under a stream of nitrogenfor 1 hour. The lipid film was dissolved over 4 minutes of vigorousvortexing in 40 mL of 176 mM K₂HPO₄/50 mM citric acid (pH 4.7)containing 7.5 μL of triton X-100, resulting in a mixed micellarpreparation with a composition of 0.32 mM triton and 0.37 mol % PS.4-Methylumbelliferyl-beta-D-glucopyranoside (ACROS-337025000) wasdissolved in the micellar solution to a final concentration of 2 mM foruse as the reaction substrate.

Test compounds were diluted to the desired concentrations withdimethylsulfoxide (DMSO) from 10 mM stocks, and 0.41 μL of the DMSOcompound mixture was added to 100 μL of micellar solution containing 10nM GCase and 100 nM saposin C (Enzo ALX-201-262-C050). Pre-incubationwas allowed to occur for 30 minutes at room temperature, after which thereaction was initiated by combining 25 μL of substrate solution with 25μL of compound/GCase/saposin mixture. The reaction proceeded for 15minutes at room temperature and was stopped by adding 150 μL of 1Mglycine, pH 12.5. The endpoint of the reaction was monitored bymeasuring fluorescence intensity (excitation: 365 nm; emission: 440 nm)on a SpectraMax i3 instrument (Molecular Devices). Test compounds werescreened at 1.0 and 0.1 M final concentration, and subsequent 8-pointdose response curves were obtained using 3-fold dilutions from a maximumfinal concentration of 5 μM.

Part II: Results

Gcase activation values for tested compounds are provided in Tables 3and 4 below, along with cLogP, PSA, and compound solubility in water.The symbol “+” indicates less than 5% Gcase activation; the symbol “++”indicates Gcase activation in the range of 5% up to 20%; and the symbol“+++” indicates Gcase activation greater than 20%. The symbol “N/A”indicates that no data available.

TABLE 3 Compound Solubility in Percent Gcase Activation Water 1 μM Test0.1 μM Test Compound Structure cLogP PSA (μg/mL) Compound Compound

4.2 66.3 16.8 + +

3.9 57.1 1.5 ++ +

4.0 57.1 3.6 ++ +

3.9 57.1 14.62 ++ +

3.4 57.1 0.7 ++ +

3.5 57.1 17.54 ++ +

3.4 57.1 15.45 + +

3.2 66.3 17.0 ++ +

2.4 78.7 1.8 +++ +

3.7 57.1 0.9 +++ ++

3.8 57.1 8.8 +++ ++

3.6 57.1 18.8 +++ +

3.5 66.3 3.9 +++ ++

4.3 57.1 7.2 +++ ++

2.9 57.1 0.3 +++ ++

4.2 66.3 3.1 +++ ++

3.9 57.1 0.3 +++ ++

2.6 57.1 15.0 ++ ++

3.3 57.1 1.8 +++ +

3.8 68.1 23.1 +++ ++

4.0 57.1 29.6 +++ +

4.1 57.1 38.4 +++ ++

4.0 57.1 2.1 +++ +++

2.8 78.7 0.4 +++ +

2.1 57.1 N/A ++ +

2.5 57.1 27.3 +++ ++

2.4 57.1 N/A +++ +

4.3 57.1 0.9 +++ ++

3.9 57.1 6.5 +++ ++

2.5 69.4 N/A +++ +

4.3 57.1 1.9 +++ (n = 2) +++ (n = 2)

4.2 57.1 0.03 +++ (n = 2) +++ (n = 2)

3.9 66.3 1.4 +++ +++

4.1 66.3 2.7 +++ (n = 2) +++ (n = 2)

3.1 69.4 6.7 +++ ++

2.7 69.4 17.2 +++ +

2.9 69.4 0.5 +++ ++

3.0 78.7 1.4 +++ +++

3.3 78.7 0.2 +++ +++

3.3 78.7 1.6 +++ ++

3.5 78.7 2.2 +++ +++

3.7 57.1 1.9 +++ ++

3.3 78.7 0.3 +++ ++

2.8 78.7 4.4 +++ +

2.8 78.7 1.3 +++ +++

3.6 80.9 0.7 +++ ++

3.1 80.9 3.9 +++ ++

3.3 80.9 2.6 +++ ++

2.5 57.1 N/A ++ +

2.9 57.1 24.0 +++ +

2.8 57.1 N/A +++ +

4.6 57.1 1.2 +++ +++

4.2 57.1 6.9 +++ ++

4.5 57.1 0.2 +++ (n = 2) +++ (n = 2)

4.6 57.1 8.0 +++ (n = 2) +++ (n = 2)

4.5 57.1 N/A N/A N/A

4.3 66.3 N/A N/A N/A

4.1 57.1 3.0 +++ ++

4.1 57.1 3.2 +++ ++

3.0 69.4 1.0 + +

3.3 66.2 0.3 ++ +

4.1 75.4 N/A ++ +

3.5 66.2 0.7 ++ +

N/A N/A N/A N/A N/A

3.4 96.9 1.4 ++ +

4.0 75.4 1.1 ++ +

4.0 41.5 N/A +++ (n = 2) +++ (n = 2)

3.9 41.5 0.1 +++ (n = 2) +++ (n = 2)

4.0 53.8 0.5 +++ (n = 2) +++ (n = 2)

3.8 53.8 1.4 +++ (n = 2) +++ (n = 2)

4.1 84.6 0.4 +++ (n = 2) +++ (n = 2)

3.4 80.9 0.2 +++ +++

2.9 60.3 8.2 +++ +++

2.6 90.1 0.7 +++ +++

TABLE 4 Compound Solubility in Percent Gcase Activation Water 1 μM Test0.1 μM Test Compound Structure cLogP PSA (μg/mL) Compound Compound

3.3 78.7 N/A +++ +++

3.3 78.7 0.5 +++ +++

2.8 78.7 1.0 +++ ++

2.8 78.7 1.2 +++ +++

3.6 80.9 N/A +++ ++

3.6 80.9 1.2 +++ +++

3.1 80.9 1.9 ++ +

3.1 80.9 1.9 +++ ++

3.3 80.9 2.3 +++ +

2.8 90.1 N/A +++ +++

2.8 90.1 N/A +++ +++

3.2 80.9 N/A +++ +++

3.2 80.9 N/A +++ +++

2.2 80.6 18.3 +++ ++

2.2 78.7 N/A +++ ++

3.1 69.4 3.5 +++ ++

3.4 69.4 3.6 +++ +++

3.4 69.4 N/A +++ ++

2.7 69.4 N/A +++ ++

3.3 69.4 0.3 +++ +++

3.3 69.4 0.3 +++ +++

2.7 69.4 1.3 +++ ++

3.1 78.7 1.5 +++ ++

3.5 60.3 N/A +++ +++

3.5 60.3 1.9 +++ +++

3.4 80.9 0.1 +++ ++

3.5 66.3 0.6 +++ +++

2.9 90.1 N/A +++ ++

2.9 90.1 0.1 +++ +++

3.4 72.7 N/A +++ ++

3.4 72.7 N/A +++ ++

3.0 69.4 N/A +++ ++

3.0 69.4 N/A +++ +

2.9 78.7 N/A +++ ++

2.9 78.7 N/A +++ ++

3.0 69.4 N/A +++ ++

3.0 69.4 N/A +++ +

2.4 88.6 N/A +++ ++

2.4 88.6 N/A +++ +

3.4 72.7 1.0 +++ ++

3.4 72.7 N/A +++ ++

3.1 80.9 N/A +++ ++

3.1 80.9 1.1 +++ ++

3.1 80.9 N/A +++ ++

3.3 80.9 0.5 +++ +++

3.3 80.9 N/A +++ ++

3.1 90.1 N/A +++ +++

4.5 57.1 0.2 +++ +++

4.5 57.1 0.2 +++ +++

4.2 57.1 0.7 +++ +++

3.6 69.4 0.7 +++ ++

3.8 69.4 N/A +++ ++

2.5 80.6 N/A +++ ++

3.2 90.1 N/A +++ ++

3.2 90.1 N/A +++ +++

3.6 80.9 N/A +++ ++

3.9 80.3 N/A +++ ++

4.2 63.1 N/A +++ +++

4.4 53.8 N/A +++ ++

4.5 53.8 N/A +++ +++

4.4 53.8 N/A +++ +++

4.3 59.9 N/A +++ ++

4.5 50.7 N/A +++ +++

4.6 50.7 N/A +++ +++

4.5 50.7 N/A +++ ++

4.0 72.3 N/A +++ ++

4.1 63.1 N/A +++ ++

4.3 63.1 N/A +++ ++

4.1 63.1 N/A +++ ++

2.9 63.1 N/A +++ +

3.1 63.1 N/A +++ ++

3.4 66.2 0.7 ++ +

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1-30. (canceled)
 31. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein: X is halogen; R¹represents independently for each occurrence C₁-C₆ alkyl, halogen, C₁-C₆haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, —(C₁-C₄ alkylene)-O—(C₁-C₆alkyl), —(C₁-C₄ alkylene)-O—(C₃-C₆ cycloalkyl), 3-6 memberedheterocyclyl, 6-membered aryl, cyano, or —N(R⁵)₂; R² is hydrogen, C₁-C₆alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, —(C₁-C₄alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄ alkylene)-O—(C₃-C₆ cycloalkyl), 3-6membered heterocyclyl, 6-membered aryl, cyano, or —N(R⁵)₂; R³ ishydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl; R⁴ is one of the following:(a) C₃-C₈ cycloalkyl substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₈ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —(C₁-C₆ alkylene)-(C₃-C₆cycloalkyl), hydroxyl, C₁-C₆ alkoxy, —O—(C₃-C₆ cycloalkyl), —O—(C₃-C₆cycloalkyl), C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, and saturated3-8 membered heterocyclyl; (b) phenyl that is (i) substituted by C₂-C₄alkynyl or —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, and (ii) optionallysubstituted by 1 or 2 substituents independently selected from the groupconsisting of C₁-C₈ alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl,—(C₁-C₆ alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆ alkoxy, —O—(C₃-C₆cycloalkyl), —O—(C₃-C₆ cycloalkyl), heteroaryl, saturated 3-8 memberedheterocyclyl, and amino; or (c) a partially unsaturated 9-10 memberedbicyclic carbocyclyl, a partially unsaturated 8-10 membered bicyclicheterocyclyl, a 9-13 membered spiroheterocycloalkyl, or —(C₂-C₆alkylene)-O-phenyl; each of which is optionally substituted by 1, 2, or3 substituents independently selected from the group consisting of C₁-C₈alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —(C₁-C₆alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, C₁-C₆ alkoxy, —O—(C₃-C₆cycloalkyl), —O—(C₃-C₆ cycloalkyl), C₂-C₄ alkynyl, —(C₂-C₄alkynyl)-C₁-C₆ alkoxy, aryl, —O-aryl, heteroaryl, saturated 3-8 memberedheterocyclyl, amino, and —CO₂R⁵; R⁵ represents independently for eachoccurrence hydrogen, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl; or twooccurrences of R⁵ attached to the same nitrogen atom are taken togetherwith the nitrogen atom to which they are attached to form a 3-8 memberedheterocyclic ring; Y is a bond, —C(O)—, C₁-C₆ alkylene, C₁-C₆haloalkylene, or C₃-C₆ cycloalkylene; and n is 0, 1, or
 2. 32. Thecompound of claim 31, wherein R¹ is C₁-C₃ alkyl.
 33. The compound ofclaim 31, wherein X is chloro.
 34. The compound of claim 31, wherein R²is hydrogen.
 35. The compound of claim 31, wherein R³ is hydrogen. 36.The compound of claim 31, wherein Y is a bond.
 37. The compound of claim31, wherein Y is C₁-C₆ alkylene.
 38. The compound of claim 31, whereinR⁴ is C₃-C₈ cycloalkyl substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁-C₈ alkyl,halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —(C₁-C₆ alkylene)-(C₃-C₆cycloalkyl), hydroxyl, C₁-C₆ alkoxy, C₂-C₄ alkynyl, —(C₂-C₄alkynyl)-C₁-C₆ alkoxy, and saturated 3-8 membered heterocyclyl.
 39. Thecompound of claim 31, wherein R⁴ is a partially unsaturated 9-10membered bicyclic carbocyclyl optionally substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁-C₆alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, hydroxyl, C₁-C₆alkoxy, C₂-C₄ alkynyl, —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy, aryl, heteroaryl,and saturated 3-8 membered heterocyclyl.
 40. The compound of claim 31,wherein R⁴ is a partially unsaturated 9-10 membered bicyclic carbocyclyloptionally substituted by C₁-C₆ alkyl.
 41. The compound of claim 31,wherein R⁴ is phenyl that is (i) substituted by C₂-C₄ alkynyl or —(C₂-C₄alkynyl)-C₁-C₆ alkoxy, and (ii) optionally substituted by 1 or 2substituents independently selected from the group consisting of C₁-C₈alkyl, halogen, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, —(C₁-C₆alkylene)-(C₃-C₆ cycloalkyl), hydroxyl, and C₁-C₆ alkoxy.
 42. Thecompound of claim 31, wherein R⁴ is phenyl substituted by C₂-C₄ alkynylor —(C₂-C₄ alkynyl)-C₁-C₆ alkoxy.
 43. The compound of claim 31, whereinn is
 0. 44-99. (canceled)
 100. A method of treating a disorder selectedfrom the group consisting of Gaucher disease, Parkinson's disease, Lewybody disease, dementia, multiple system atrophy, epilepsy, bipolardisorder, schizophrenia, an anxiety disorder, major depression,polycystic kidney disease, type 2 diabetes, open angle glaucoma,multiple sclerosis, endometriosis, and multiple myeloma, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of claim 31 to treat the disorder.
 101. The methodof claim 100, wherein the disorder is Parkinson's disease.
 102. Themethod of claim 100, wherein the disorder is Lewy body disease.
 103. Acompound selected from the group consisting of


104. A method of treating a disorder selected from the group consistingof Gaucher disease, Parkinson's disease, Lewy body disease, dementia,multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, ananxiety disorder, major depression, polycystic kidney disease, type 2diabetes, open angle glaucoma, multiple sclerosis, endometriosis, andmultiple myeloma, comprising administering to a patient in need thereofa therapeutically effective amount of a compound of claim 103 to treatthe disorder.
 105. The method of claim 104, wherein the disorder isParkinson's disease.
 106. The method of claim 104, wherein the disorderis Lewy body disease.